NURS 502 SUAGM Contralateral Prophylactic Mastectomy Discussion

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Surgical Oncology 29 (2019) 126–133 Contents lists available at ScienceDirect Surgical Oncology journal homepage: www.elsevier.com/locate/suronc Residual glandular tissue (RGT) in BRCA1/2 germline mutation carriers with unilateral and bilateral prophylactic mastectomies T Olga Grinsteina,1, Barbara Kruga,∗,1, Martin Hellmicb, Florian Siedeka, Wolfram Malterd, Christina Burkea, Rita Schmutzlerc, David Maintza, Kerstin Rhiemc a Department of Diagnostic and Interventional Radiology, University Hospital of Cologne, Germany Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital of Cologne, Germany b Institute of Medical Statistics and Bioinformatics, University of Cologne, Germany d Breast Center, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Germany c A R T I C LE I N FO A B S T R A C T Keywords: Residual glandular tissue Breast magnetic resonance imaging Breast cancer BRCA1 BRCA2 Prophylactic mastectomy Background: Prophylactic mastectomy (PME) is increasingly performed in women carrying deleterious BRCA1 and BRCA2 germline mutations. The oncologic risk resulting from residual fibroglandular tissue (RGT) is unknown. Methods: All women who had received a mastectomy and at least one postoperative breast MRI, between 2006 and 2016 were extracted from the register of the Center for Hereditary Breast and Ovarian Cancer Cologne (CHBOC). The index MRI was evaluated in terms of basic clinical data and the morphological criteria of RGT. The RGT volume was measured in diameter and was semi-automatically evaluated using software. Results: We identified 169 women carrying BRCA1/2 mutations who underwent prophylactic and curative mastectomy: a total of 338 breasts. RGT was found in 128 of the 338 breasts (37.9%). 68 of the 128 breasts (53.1%) were related to bilateral PME, 37 (28.9%) to unilateral PME and 23 (18.0%) to curative mastectomy. RGT was predominantly unifocal and located in the retroareolar breast region. RGT was observed more often after bilateral PME (p < 0.0001). In this subgroup, the nipple-sparing mastectomy dominated (108 of 136, 79.4%), in contrast to 23 standard mastectomies (23 of 94, 24.5%) in the subgroup of curative mastectomy (23%). There was a trend towards higher amounts of RGT in surgical units with fewer mastectomies performed. During follow-up, two breast cancers were detected after bilateral and unilateral PME, respectively. Conclusions: Our results suggest that the indication for surgery and in particular the selected surgical procedure affect the surgical outcome with respect to RGT. Oncological safety should not be neglected, especially in the high-risk group of BRCA1/2 mutation carriers. 1. Purpose The risk of developing breast cancer by the age of 80 is estimated to be 44% to 79% for BRCA1 mutation carriers and 18%–77% for BRCA2 mutation carriers [1,2]. The risk of developing metachronous contralateral breast cancer is also increased depending on the mutated gene and the age of the patient at diagnosis [3,4]. BRCA1 mutation carriers have a 30% higher mortality rate compared to patients with BRCA1 negative and sporadic breast cancer [5]. BRCA2 mutation carriers have a 29% poorer breast cancer specific survival compared to BRCA2 negative breast cancer patients [5]. The relevance of structured, image-based surveillance is undisputed in the light of this background [6–10]. The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), founded in 1996 by the German Cancer Aid, today comprises 19 specialized university centers throughout Germany. Since 2005 it has offered women at risk of breast cancer not only a detailed consultation with risk calculation and genetic testing but also a structured image-based surveillance program which includes an annual breast MRI [11,12]. As an alternative to participating in this image-based surveillance program, bilateral prophylactic mastectomy (PME) in healthy BRCA1/2 mutation carriers and unilateral PME in BRCA1/2 mutation carriers with history of contralateral breast cancer represent potential risk reducing options [13,14]. Women undergoing bilateral PME in the GC-HBOC program ∗ Corresponding author. Department of Diagnostic and Interventional Radiology, University Hospital of Cologne, Kerpener Straße 62, 50924, Cologne, Germany. E-mail address: Barbara.krug@uk-koeln.de (B. Krug). 1 contributed equally. https://doi.org/10.1016/j.suronc.2019.04.009 Received 25 October 2018; Received in revised form 21 March 2019; Accepted 29 April 2019 0960-7404/ © 2019 Elsevier Ltd. All rights reserved. Surgical Oncology 29 (2019) 126–133 O. Grinstein, et al. mastectomy and the first one after were included in the evaluations. The image documentation and follow-up were taken from the Picture Archiving and Communication System (PACS) of the University Hospital (ImpaxEE®, AGFA Healthcare, NV, Mortsel, Belgium). have at least one breast MRI following the surgical procedure in order to ensure that there is no relevant residual glandular tissue (RGT) remaining warranting further MRI surveillance. The nipple-areola complex (NAC) is preserved in the majority of PME for aesthetic reasons primarily, whereas in skin-sparing mastectomies, mainly carried out for curative indications, the glandular tissue and the NAC are removed leaving only the skin and a thin layer of subcutaneous fat and tissue to maintain vascularization [15,16]. The results published to date show a significant risk reduction for breast cancer in PME using different surgical techniques in the high-risk group of BRCA1 and BRCA2 mutation carriers [17–19]. Contralateral PME after unilateral breast cancer has also been associated with a significant risk reduction for metachronous breast cancer [13,18]. Contrarily, the analysis of breast cancer mortality rates did not indicate a benefit after PME compared to women who had not undergone PME [13,18]. Initial data published by Heemskerk-Gerritsen BAM et al., in 2015 suggest a survival benefit after contralateral PME [13]. There is currently a lack of long-term studies, which provide a sound evaluation of oncological safety concerning PME. The risk of developing breast cancer after PME is influenced significantly by the remaining RGT. Currently, there exist only few data on the detection rates of RGT with predominantly histopathological approaches, small patient numbers ranging between 27 and 90 patients and detection rates of RGT between 5% and 61% [20–23]. The aims of this study were 2.3. MR examination techniques Between 2006 and 2014, breast MRIs were performed using an open whole-body MRI scanner of 1.0 T main magnetic field strength (Panorama 1.0, Philips Healthcare, Best, The Netherlands) and using a whole-body MRI scanner of 1.5 T main magnetic field strength (Achieva 1.5, Philips Healthcare) with dedicated 4-channel and 7-channel breast coils. Since 2015 all breast MRIs have been acquired using whole-body MRI scanners of 1.5 T or 3.0 T magnetic field strength (Ingenia 1.5 and Ingenia 3.0, Philips Healthcare) with 16-channel breast coils. In addition, diffusion imaging was introduced into the standard protocol in 2015. Gadoteric acid (Dotarem®, Guerbet GmbH, Sulzbach/Taunus, Germany) was used as intravenous contrast agent in a weight-adapted dose of 0.2 ml/kg body weight in all examinations. The T2-weighted sequences were used in axial orientation to determine RGT and skin flap thickness. The dynamic, contrast-enhanced 3D T1-weighted scan was acquired at six time points up until 2015 and thereafter only at points 0, 30 s, 120 s and 210 s after injection of contrast agent bolus. • to describe frequency, localization and volume of RGT after bilateral PME, unilateral PME and curative mastectomy using breast MRI, • to define risk constellations, in which RGT must be expected more frequently and • to analyze the occurrence of primary breast cancer after PME during 2.4. Image analysis The retrospective evaluation of the breast MRI-image data was performed at a dedicated RIS-PACS workstation (ImpaxEE®, AGFA Healthcare). As a first step, two radiologists (OG, BK) evaluated the electronic image data regarding the presence of RGT and other postoperative changes independently from each other using an electronic questionnaire. In the case of RGT localization, MRI tissue characteristics such as ACR-grade and parenchymal background enhancement were recorded. Postoperative changes such as scars, liponecrosis and seromas were also noted. The thickness of the subcutaneous tissue was measured bilaterally at two opposing sites (3 o'clock and 9 o'clock, respectively). As a second step conflicting classifications were discussed between the two readers and a consensus was found. As a third step the maximum sagittal (a), transverse (b) and coronal (c) diameters of RGT in a Cartesian system were independently assessed by three radiologists (BK, OG, FS). The RGT volume (V) then was extrapolated using the geometric formula of an ellipsoid (V = 4/3πabc). As a fourth step, the RGT volume was calculated semi-automatically using special software (Intellispace®, Philips Healthcare) by three evaluators (KA, BK, OG). The results of the two volumetric techniques were collected using a structured electronic questionnaire (Excel®, Microsoft Corp., Redmond, WA, USA). clinical follow-up. 2. Materials und methods 2.1. Inclusion and exclusion criteria The study protocol was approved by the Local Ethics Committee. All participants of the university's Center for Hereditary Breast and Ovarian Cancer Cologne (CHBOC) who underwent unilateral or bilateral PME and received at least one postoperative breast MRI for proof or exclusion of RGT at the Radiology Department of the University Hospital of Cologne, Germany, from January 1st, 2006 to December 31st, 2016 were included in the study. We excluded all participants • who had breast MRI's at other centers of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), • without a postoperative breast MRI, • whose postoperative breast MRI was performed at another clinical site • without pathogenic BRCA1/2 germline mutation. 2.2. Patient and examination characteristics 2.5. Statistical analysis The patient data, as well as the genomic and clinical data, were obtained from the electronic register of the CHBOC, the HospitalInformation-System (HIS) (ORBIS® OpenMed, AGFA HealthCare, NV, Mortsel, Belgium) and the Radiology-Information-System (RIS-Nice®, AGFA HealthCare, NV, Mortsel, Belgium) of the University Hospital. Two radiologists (OG, BK) checked the registries and HIS-/RIS-recordings in reference to the patient's clinical status (bilateral vs. unilateral PME). In the case of a unilateral PME, the status of the contralateral breast was recorded (curative mastectomy vs. breast conserving therapy). Concurrently, it was noted whether and, if so, at what time before and/or after the mastectomy a breast MRI was performed in the University Hospital. The last breast MRI performed before the The evaluators' assessments were documented in a customized spreadsheet (Excel®, Microsoft Corp., Redmond, WA, USA). Quantitative variables were summarized by median and interquartile range (IQR, 25th to 75th percentile), qualitative variables by absolute and relative frequency (%). Bland-Altman or scatter plots were used for data illustration. Relationships were described by linear regression and Pearson's correlation coefficient. Volumes between patient subgroups were compared using the non-parametric Mann-Whitney U test, proportions using Fisher's exact test. In the essential exploratory analysis pvalues < 0.05 were considered statistically significant. Calculations were carried out using SPSS Statistics software (IBM Corp., Armonk, NY, USA). 127 Surgical Oncology 29 (2019) 126–133 O. Grinstein, et al. Table 1 Aggregated results classified according to the number of mastectomies carried out per surgical institution.. Number of ME per institution Criteruin; Median (IQR) or n (%) Prophylactic Healthy ME Prophylactic Diseased ME Curative ME 0–20 Breast volume prior to ME, ml Breast volume after ME, ml Width of subcutaneous tissue, mm Sagittal diameter of RGT, mm Residual retroareolar breast tissue Sagittal diameter of (all) RGT: 0 mm Sagittal diameter of (all) RGT: < 5 mm Sagittal diameter of (all) RGT: ≥5 mm ACR II: glandular/fatty tissue 25% - < 50% ACR III: glandular/fatty tissue 50% - < 75% Breast volume prior to ME, ml Breast volume after ME, ml Width of subcutaneous tissue, mm Sagittal diameter of RGT, mm Residual retroareolar breast tissue Sagittal diameter of (all) RGT: 0 mm Sagittal diameter of (all) RGT: < 5 mm Sagittal diameter of (all) RGT: ≥5 mm ACR II: glandular/fatty tissue 25% - < 50% ACR III: glandular/fatty tissue 50% - < 75% Breast volume prior to ME, ml Breast volume after ME, ml Width of subcutaneous tissue, mm Sagittal diameter of RGT, mm Residual retroareolar breast tissue Sagittal diameter of (all) RGT: 0 mm Sagittal diameter of (all) RGT: < 5 mm Sagittal diameter of (all) RGT: ≥5 mm ACR I: glandular/fatty tissue < 25% ACR II: glandular/fatty tissue 25% - < 50% ACR III: glandular/fatty tissue 50% - < 75% Breast volume prior to ME, ml Breast volume after ME, ml Width of subcutaneous tissue, mm Sagittal diameter of RGT, mm Residual retroareolar breast tissue Sagittal diameter of (all) RGT: 0 mm Sagittal diameter of (all) RGT: < 5 mm Sagittal diameter of (all) RGT: ≥5 mm ACR I: glandular/fatty tissue < 25% ACR II: glandular/fatty tissue 25% - < 50% ACR III: glandular/fatty tissue 50% - < 75% 133 (70–182) 4 (3–7) 9 (7–13) 3 (0–7) 35/68 (51.5%) 30/68 (44.1%) 9/68 (13.2%) 29/68 (42.6%) 16/38 (42.1%) 22/38 (57.9%) 104 (63–140) 4 (3–5) 7 (5–11) 0 (0–5) 8/26 (30.8%) 18/26 (69.2%) 2/26 (7.7%) 6/26 (23.1%) 6/8 (75%) 2/8 (25%) 54 (40–111) 3 (2–4) 10 (8–17) 3 (0–7) 24/44 (54.5%) 20/44 (45.5%) 7/44 (15.9%) 17/44 (38.6%) 0/24 (0%) 16/24 (66.7%) 8/24 (33.3%) 92 (55–172) 3 (3–6) 9 (7–13) 2 (0–7) 67/138 (48.6%) 68/138 (49.3%) 18/138 (13%) 52/138 (37.7%) 0/70 (0%) 38/70 (54.3%) 32/70 (45.7%) 108 (93–151) 2 (2–3) 9 (7–14) 0 (0–5) 14/39 (35.9%) 25/39 (64.1%) 5/39 (12.8%) 9/39 (23.1%) 6/14 (42.9%) 8/14 (57.1%) 71 (66–93) 2 (2–2) 9 (5–15) 0 (0–7) 5/12 (41.7%) 7/12 (58.3%) 0/12 (0%) 5/12 (41.7%) 3/5 (60%) 2/5 (40%) 109 (53–228) 2 (1–4) 11 (7–14) 0 (0–4) 15/48 (31.3%) 31/49 (63.3%) 6/49 (12.2%) 12/49 (24.5%) 2/18 (11.1%) 6/18 (33.3%) 10/18 (55.6%) 93 (65–151) 2 (2–3) 10 (7–14) 0 (0–5) 34/99 (34.3%) 63/100 (63%) 11/100 (11%) 26/100 (26%) 1/37 (2.7%) 15/37 (40.5%) 20/37 (54.1%) 106 (106–106) 3 (2–4) 8 (6–13) 0 (0–0) 7/38 (18.4%) 31/38 (81.6%) 2/38 (5.3%) 5/38 (13.2%) 4/7 (57.1%) 3/7 (42.9%) 29 (29–29) 1 (1–1) 4 (3–13) 0 (0–0) 1/12 (8.3%) 11/12 (91.7%) 0/12 (0%) 1/12 (8.3%) 1/1 (100%) 0/1 (0%) 126 (61–209) 4 (1–5) 10 (6–13) 0 (0–5) 13/49 (26.5%) 35/50 (70%) 3/50 (6%) 12/50 (24%) 0/15 (0%) 3/15 (20%) 12/15 (80%) 124 (61–155) 3 (1–5) 9 (5–13) 0 (0–0) 21/99 (21.2%) 77/100 (77%) 5/100 (5%) 18/100 (18%) 0/23 (0%) 8/23 (34.8%) 15/23 (65.2%) 40–60 > 60 total Abbreviations:ME ‘mastectomy’ RGT ‘residual glandular tissue’ IQR ‘interquartile range (25th to 75th percentile)’. 3. Results 3.2. Surgical units 3.1. Study group The 262 mastectomies were performed in 41 hospitals. Concerning 76 mastectomies the surgical center was not apparent from the available registers. The units were divided into three groups: 0–20 mastectomies per unit, 40–60 mastectomies per unit, > 60 mastectomies per unit. The subgroup analyses showed a significantly higher RGT volume following mastectomies in the surgical units with 0–20 mastectomies compared to those with ≥40 mastectomies (p < 0.033). The proportion of RGT present following bilateral PME (subgroup A) and curative mastectomy (subgroup C) was also higher in less frequented units (0–20 mastectomies/unit versus 40–60 mastectomies/unit): subgroup A 51.5% versus 30.8%, subgroup B 35.9% versus 41.7%, subgroup C 18.4% versus 8.3% (Table 1). 169 women met the inclusion criteria and did not fall under any of the exclusion criteria (Table 1, supplementary data). Thus, the evaluations were based on 338 MR-tomographically examined breasts in 169 women with BRCA1/2 mutations. The median age of the 69 patients included with bilateral PME was 38.3 years ± 8.9 years standard deviation (minimum 21.2 years, maximum 58.6 years) and 42.3 years ± 8.4 years standard deviation (minimum 21.5 years, maximum 62.4 years) for the 100 patients with unilateral PME. All 100 patients with unilateral PME (100%) had either an immediate or a delayed curative mastectomy. The mastectomized breasts were analyzed separately and subdivided into the following subgroups: 3.3. Surgical techniques 1. Subgroup A: bilateral PME in healthy mutation carriers (138 breasts in 69 patients) 2. Subgroup B: unilateral PME of the healthy breast in mutation carriers with contralateral breast cancer (100 breasts in 100 patients) 3. Subgroup C: curative mastectomy of the diseased breasts (100 breasts in 100 patients). According to the data of the CHBOC register, of the 338 breasts operated on (169 women), 283 breasts (83.8%) underwent skin or nipple-sparing mastectomy and 41 breasts (12.1%) underwent modified standard mastectomy, namely removal of the breast and nipple, 31 of which had secondary breast reconstruction and 10 did not. In 14 breasts (4.1%), it was unclear whether the surgical method was skin/nipple sparing or standard mastectomy with no reconstruction due to the 128 Surgical Oncology 29 (2019) 126–133 O. Grinstein, et al. Fig. 1. Graphical representation of the depth of RGT in the sagittal “areola to thoracic wall” plane depending on the surgical technique used in bilateral PME (subgroup A), unilateral PME in contralaterally diseased women (subgroup B) and curative mastectomies in women with contralateral PME (subgroup C). Circle = statistical outlier, asterisk = numeric extreme value. Fig. 2. Bland-Altmann plot comparing the volumetric (software-based) and Cartesian (diameter-based) determinations of RGT in 128 breasts. The abscissa represents the mean of both determinations per breast and the ordinate represents the difference between the two determinations. It shows limits of agreement of −3.8 to 5.7 (ml) with bias of 0.95 (95% CI 0.53 to 1.38, p < 0.001) towards larger volumes for the software-based method compared to the volumetric method. retrospective methodological approach and the inclusion of 41 breast units which implemented different documentation standards. In subgroup A (bilateral PME) nipple sparing mastectomies were performed in 108 (78.3%) and skin sparing mastectomies were carried out in 18 (13.0%) of 136 cases. Concerning eight breasts the surgical technique was specified as either nipple sparing or skin-sparing (Fig. 1, supplementary data). Two breasts underwent standard mastectomy without reconstruction (1.4%). In two cases, no information was given on the surgical technique. In subgroup B (unilateral PME) 16 out of 100 breasts (16.0%) and in subgroup C (unilateral curative mastectomy) 23 out of 100 breasts (23.0%) had a standard mastectomy without reconstruction. 53 of the 100 unilateral PMEs (53.0%) and 46 of the 100 curative mastectomies (46.0%) were performed using nipple sparing technique. There were 22 skin sparing mastectomies (22.0%) and three mastectomies (3.0%) without further specification in subgroup B and subgroup C, respectively. In six cases the CHBOC register did not provide any information on the surgical technique used. 3.4. vol calculation techniques Fig. 2 shows the results of the manually performed volume calculations by Cartesian determinations of the maximum diameter (step 3) compared with the results of the semi-automatic software-based calculations (step 4) in the form of a Bland-Altmann-Plot. For the softwarebased method an above-average standard deviation towards larger volumes was found compared to the volumetric method. In the following, the software-based volumetric results were used. Fig. 3. Statistical outlier: 38 year-old patient who had undergone bilateral PME for a pathogen BRCA1/2 germline mutation and bilateral reconstruction with silicone prostheses in 2013. Breast volume measured 83 ml (right side) and 105 ml (left side) preoperatively and 78 ml (right side) and 57 ml (left side) post PME. 3.5. Frequency of RGT Overall, RGT was detected in 128 of the 338 breasts following mastectomy (37.9%). 68 of the 128 breasts (53.1%) were related to bilateral PME (subgroup A), 37 breasts (28.9%) to unilateral PME (subgroup B) and 23 (18%) to curative mastectomy (subgroup C). RGT appeared significantly more often after bilateral PME than unilateral PME (p < 0.0001). The comparison of subgroup A and subgroup C did not show a statistically significant difference (p < 0.102), neither did the comparison of subgroup B and subgroup C (p < 0.199), which may have been due to the low number of cases (Table 1). 3.5.1. RGT volume before and after mastectomy The postoperative volumes in subgroup A averaged 3 ml (minimum 3 ml, maximum 6 ml), in subgroup B 2 ml (2 ml, 3 ml), in subgroup C 3 ml (1 ml, 5 ml) (Fig. 3). In 79 of the 128 breasts with RGT preoperative MRI scans were available. The results of a patient with average preoperative volumes (right breast 83 ml, left breast 105 ml) and postoperative RGT volumes of 78 ml on the right side and 57 ml on 129 Surgical Oncology 29 (2019) 126–133 O. Grinstein, et al. Fig. 4. Graphical representation of the volume of preoperative breast tissue on the abscissa and the RGT after mastectomy on the ordinate per breast (red dots) in patients with both preoperative and postoperative breast MRI. A positive correlation is shown between preoperative breast volume and RGT volume when considering all 76 breasts (Fig. 4A), the subgroup of bilateral PME ( Fig. 4B), the subgroup with unilateral PME ( Fig. 4C) and the subgroup with curative mastectomy ( Fig 4D) (p < 0.001). Three outliers with RGT of 78 ml, 57 ml and 29 ml after bilateral PME (blue dots) were excluded from statistical analysis. A All 76 breasts with RGT and preoperative breast MRI B 52 breasts with bilateral PME C 15 breasts with unilateral PME D Nine breasts with curative mastectomy. Fig. 5. Graphical representation of the width of the postoperative soft tissue on the ordinate and the preoperative gland volume on the abscissa divided into two groups: retroareolar RGT < 5 mm in the sagittal diameter (left) and ≥5 mm (right) demonstrating a significant reduction of soft tissue in bigger preoperative volumes in the second group (right). 3.5.2. Localization of RGT In 122 of the 128 breasts affected, the RGT was localized in the retroareolar breast region (94.6%). In subgroup A the RGT was detected in the retroareolar breast region in 67 out of 70 cases (95.7%), in subgroup B in 34 out of 36 cases (94.4%) and in subgroup C in 21 out of 23 cases (91.3%). Independent of subgroup allocation, retroareolar left side were excluded from the statistical calculations as statistical outliers. The regression analysis confirmed a linear relationship between the RGT volume before and after mastectomy across all subgroups as well as in the independently analyzed subgroups, indicating that larger preoperative baseline volumes contain more RGT post mastectomy (Fig. 4A–D). 130 Surgical Oncology 29 (2019) 126–133 O. Grinstein, et al. localized mainly in the retroareolar breast region (122 of 128 breasts) with multifocal RGT being an exception and concerning only 10% of the bilaterally mastectomized breasts (seven breasts). While 97.1% of the bilateral PMEs were carried out using skin or nipple-sparing technique, 16% of the unilateral PMEs and 23% of the curative mastectomies were carried out using standard mastectomy technique with and without reconstruction. Therefore, RGT is a common postoperative finding that appears to be related to the selected surgical technique. In accordance with the present results Woitek et al. evaluated postoperative MRI scans of 58 patients after prophylactic skin-sparing mastectomy (SSM) and nipple-sparing mastectomy (NSM) and found RGT in 20% of all breasts and significantly more frequently after NSM than SSM [24]. Van Verschuer et al. histologically analyzed 105 NippleAreola-Complexes (NACs) and adjacent skin islands in 90 women after prophylactic skin-sparing (31 cases) and curative mastectomies (71 cases). They found evidence of RGT in 61% of the NAC samples and 24% of the skin samples but did not differentiate between the two surgical indications [23]. In the present study, a significantly higher RGT volume was found in breasts mastectomized in the less frequented surgical units with > 20 mastectomies compared to those with ≥40 mastectomies (p < 0.033), which indicates that the individual surgeon's expertise or the cumulative team experience has a marked impact on the clinical outcome. For the two-point measurements (horizontal direction, 3 o'clock and 9 o'clock), the thickness of the subcutaneous tissue averaged 10.5 mm with maximum values of 52.3 mm. In accordance with our approach Zippel et al. used postoperative MRI to evaluate residual breast tissue in 88 breasts after prophylactic (n = 43) and curative mastectomies (n = 45) and reconstruction using silicone prostheses at four points with similarly high mean and maximum values (mean 11.2 mm, maximum 53.4 mm) [25]. Additionally, there was an association between the thickness of the subcutaneous tissue and RGT volume, especially at locations other than the retroareolar breast region. These findings are concordant with the histological results of Torresan et al. who showed a significant association (p < 0.005) between the presence of RGT and skin flap thickness of more than 5 mm [22]. The sagittal diameter of retroareolar RGT was ≥5 mm in 96 of the 130 mastectomzied breasts (74%) and thus exceeded the recommended 5 mm limit for the maintenance of subdermal vascularization [26,27]. The mean and maximum diameters were larger after bilateral PME when compared with unilateral PME and curative mastectomy. These results support the hypothesis that different surgical indications and chosen techniques influence the clincial outcome significantly. Baltzer et al. used breast MRI to measure the retroareolar fibroglandular tissue relative to the entire glandular body at 5 mm and 10 mm retroareolar diameters on a total of 105 BRCA1/2 mutation carriers [28]. The proportion of retroareolar glandular tissue assuming a sagittal diameter of 5 mm averaged only 1.3% of the total glandular tissue. However, increasing the diameter to 1 cm showed a highly significant increase of the proportion to 3% (p < 0.001). Even a proportion of 1.3% appears clinically relevant taking into account the fact that both carcinomas we detected during the follow_up appeared as microscopically undetectable RGT. The median time to follow-up was 4.3 years (minimum 6 months and maximum 19 years). Two out of 169 women developed breast cancer following PME after two and five years, respectively. Despite the use of nipple-sparing technique (78.3% in subgroup A), no carcinoma was observed in the retroareolar breast region. This is in accordance with the results of the multi-center study by Orzalesi et al. who found following 1006 nipple-sparing mastectomies (12.3% PME), recurrence of cancer in the NAC in 0.7% over a mean follow-up period of 1101 days [29]. Yao et al. analyzed 397 nipple-sparing mastectomies in BRCA1/2 mutation carriers (74.6% PME) with a total of four breast cancers (one carcinoma after PME) on average in the follow-up period of 32.6 months, with no NAC involvement [30]. Manning et al. did not record any oncological events after a total of 177 nipple-sparing RGT was most often found following nipple sparing mastectomy (Fig. 1). Multifocal RGT was an exception and concerned only seven breasts in subgroup A (10%). In subgroup B and subgroup C, there was no case of multifocal RGT. 3.5.3. Sagittal diameter of RGT The retroareolar extension of RGT, defined as the sagittal RGT diameter measured between the areola and the thoracic wall, averaged 2 mm (minimum 0 mm, maximum 7 mm) in subgroup A, 0 mm (0 mm, 5 mm) in subgroup B and 0 mm (0 mm, 0 mm) in subgroup C. In subgroup A 52 of the 138 breasts showed RGT with a sagittal diameter of ≥5 mm (37.7%), in subgroup B 26 of the 100 breasts showed such a diameter (26%) and in subgroup C 18 of the 100 breasts (18%) were found to have RGT with ≥5 mm sagittal diameter (Table 1). A sagittal RGT diameter ≥5 mm showed a significant correlation between the thickness of the subcutaneous tissue and the preoperative initial volume with increasingly narrow flap at larger initial volumes (Fig. 5). 3.5.4. Thickness of the subcutaneous tissue The mean thickness of the subcutaneous tissue was 9 mm (minimum 7 mm, maximum 13 mm) in subgroup A, 10 mm (7 mm, 14 mm) in subgroup B and 9 mm (5 mm, 13 mm) in subgroup C (Table 1). The regression analysis of RGT and the postoperative subcutaneous soft tissue showed a positive trend towards larger RGT volumes in thicker soft tissue flaps (Fig. 6). RGT in the retroareolar breast region showed a negative trend towards narrower soft-tissue flaps in breasts with larger initial volumes (Fig. 7). 3.6. Clinical follow-up The median time to follow-up under the CHBOC program was 4.3 years (minimum six months, maximum 19 years). Breast cancers were recorded in two patients five years after bilateral PME and two years after unilateral PME respectively in locations without RGT as visualized by the index breast MRI. In the first case of retroareolar RGT, in the index-MRI, the carcinoma was located in the periphery of the left upper outer quadrant according to the clinical documentation. In the second case there was no RGT visualized in the index-MRI. 4. Discussion In the present study, RGT was detected in 128 of 338 mastectomized breasts (37.9%). In more than 50% (68 of 128 breasts), RGT was related to bilateral PME and was present significantly more often after bilateral PME than after unilateral PME and curative mastectomy. RGT was Fig. 6. Correlation of the width of the postoperative soft tissue (plotted on the ordinate) and the postoperative RGT (plotted on the abscissa), including all three subgroups demonstrating a positive trend. 131 Surgical Oncology 29 (2019) 126–133 O. Grinstein, et al. Fig. 7. Comparison of the thickness of the postoperative soft tissue (ordinate) and the preoperative gland volume (abscissa) divided into two groups: RGT localization other than in retroareolar breast region (left) and RGT in the retroareolar breast region (right) demonstrating a negative trend in the second group. outcome. In view of these findings, radiologists should report on RGT more consistently and the continuation of structured image-based surveillance of BRCA1/2 mutation carriers has to be discussed even following PME if RGT persists. However, large-scale, prospective, longterm studies are needed in order to assess the oncological risk associated with RGT and to define the role of breast MRI in the management of patients following PME. mastectomies in BRCA 1/2 mutation carriers during an average followup period of 2.15 years [31]. However, the short follow-up period is indeed a mentionable limitation of these studies. Hartmann et al. followed-up 639 women at increased hereditary risk for breast cancer, who underwent PME, for a median of 14 years [32]. Seven of these women developed breast cancer 2–25 years after mastectomy, only one of them in the NAC. Skytte et al. surveyed 307 healthy BRCA1/2 mutation carriers; 96 of them having undergone bilateral PME [33]. Three of them developed breast cancer at intervals of two, five and seven years after PME. Two of the carcinomas were located on the thoracic wall and one in the axilla. Based on those results, the working group calculated a cumulative ten-year incidence for the cohort of mastectomized mutation carriers of about 10%. Since no image correlation took place in these studies, it prompts the question about underlying RGT. The present study has the following methodological limitations: Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.suronc.2019.04.009. References [1] A. Antoniou, P.D.P. Pharoah, S. Narod, H.A. Risch, J.E. Eyfjord, J.L. Hopper, et al., Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies, Am. J. Hum. Genet. 72 (5) (2003 May) 1117–1130. [2] K.B. Kuchenbaecker, J.L. Hopper, D.R. Barnes, K.-A. Phillips, T.M. Mooij, M.J. Roos-Blom, et al., Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers, JAMA 317 (23) (2017 Jun 20) 2402–2416. [3] M.K. Graeser, C. Engel, K. Rhiem, D. Gadzicki, U. Bick, K. Kast, U.G. Froster, B. Schlehe, A. Bechtold, N. Arnold, S. Preisler-Adams, C. Nestle-Kraemling, M. Zaino, M. Loeffler, M. Kiechle, A. Meindl, D. Varga, R.K. Schmutzler, Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers, J. Clin. Oncol. 27 (35) (2009 Dec 10) 5887–5892, https://doi.org/10.1200/JCO.2008.19. 9430 Epub 2009 Oct 26. [4] K. Rhiem, C. Engel, M. Graeser, S. Zachariae, K. Kast, M. Kiechle, N. Ditsch, W. Janni, C. Mundhenke, M. Golatta, D. Varga, S. Preisler-Adams, T. Heinrich, U. Bick, D. Gadzicki, S. Briest, A. Meindl, R.K. Schmutzler, The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study, Breast Cancer Res. 14 (6) (2012 Dec 7) R156, https://doi.org/10.1186/bcr3369. [5] Z. Baretta, S. Mocellin, E. Goldin, O.I. Olopade, D. Huo, Effect of BRCA germline mutations on breast cancer prognosis: a systematic review and meta-analysis, Medicine (Baltim.) 95 (40) (2016 Oct) e4975. [6] D. Saslow, C. Boetes, W. Burke, S. Harms, M.O. Leach, C.D. Lehman, et al., American cancer society guidelines for breast screening with MRI as an adjunct to mammography, CA A Cancer J. Clin. 57 (2) (2007 Mar 1) 75–89. [7] U. Bick, Intensified surveillance for early detection of breast cancer in high-risk patients, Breast Care Basel Switz 10 (1) (2015 Feb) 13–20. [8] E.B. Mendelson, J.K. Baum, W.A. Berg, et al., Breast Imaging Reporting and Data System, ACR BI-RADS—breast Imaging Atlas vol. 2003, American College of Radiology, Reston, VA, 2003. [9] Breast Imaging Working Group of the German Radiological Society, Updated recommendations for MRI of the breast, ROFO Fortschr Geb Rontgenstr Nuklearmed 186 (5) (2014 May) 482–483. [10] F. Cardoso, S. Loibl, O. Pagani, A. Graziottin, P. Panizza, L. Martincich, et al., The • Long-term follow-up was only possible in a subgroup of patients, • because quite a number of women left the screening program after the first postoperative follow-up and/or because the time interval between mastectomy and the evaluations was rather short. Some oncological events might have been missed for this reason. The volume measurements of RGT were hampered by the fact that in particularly fatty breasts and in breasts with only scattered areas of fibroglandular density, the exact discrimination of glandular tissue, subcutaneous septae and postoperative scars was difficult. Due to the limited spatial resolution of breast MRI, small glandular bonds at cellular level, which may be the origin of breast cancer, cannot be visualized by breast MRI. Further prospective studies are warranted in order to answer the question as to whether long-term MRI surveillance in women with an increased risk of breast cancer following bilateral PME is advisable. 5. Conclusions RGT is a common finding after PME and curative mastectomy that varies depending on the surgical indication and the chosen surgical procedure in individual patients. 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Pfeiler, A. Farr, P. Kapetas, J. Furtner, M. Bernathova, et al., MRIbased quantification of residual fibroglandular tissue of the breast after conservative mastectomies, Eur. J. Radiol. 104 (2018 Jul) 1–7. [25] D. Zippel, V. Tsehmaister-Abitbol, A. Rundstein, A. Shalmon, A. Zbar, G. Nardini, et al., Magnetic resonance imaging (MRI) evaluation of residual breast tissue following mastectomy and reconstruction with silicone implants, Clin. Imaging 39 (3) (2015 Jun) 408–411. [26] Z.K. Algaithy, J.Y. Petit, V. Lohsiriwat, P. Maisonneuve, P.C. Rey, N. Baros, et al., Nipple sparing mastectomy: can we predict the factors predisposing to necrosis? Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol 38 (2) (2012 Feb) 125–129. [27] V. Sacchini, J.A. Pinotti, A.C.S.D. Barros, A. Luini, A. Pluchinotta, M. Pinotti, et al., Nipple-sparing mastectomy for breast cancer and risk reduction: oncologic or technical problem? J. Am. Coll. Surg. 203 (5) (2006 Nov) 704–714. [28] H.L. Baltzer, O. Alonzo-Proulx, J.G. Mainprize, M.J. Yaffe, K.A. Metcalfe, S.A. Narod, et al., MRI volumetric analysis of breast fibroglandular tissue to assess risk of the spared nipple in BRCA1 and BRCA2 mutation carriers, Ann. Surg. Oncol. 21 (5) (2014 May) 1583–1588. [29] L. Orzalesi, D. Casella, C. Santi, L. Cecconi, R. Murgo, S. Rinaldi, et al., Nipple sparing mastectomy: surgical and oncological outcomes from a national multicentric registry with 913 patients (1006 cases) over a six year period, Breast Edinb Scotl 25 (2016 Feb) 75–81. [30] K. Yao, E. Liederbach, R. Tang, L. Lei, T. Czechura, M. Sisco, et al., Nipple-sparing mastectomy in BRCA1/2 mutation carriers: an interim analysis and review of the literature, Ann. Surg. Oncol. 22 (2) (2015 Feb) 370–376. [31] A.T. Manning, C. Wood, A. Eaton, M. Stempel, D. Capko, A. Pusic, et al., Nipplesparing mastectomy in patients with BRCA1/2 mutations and variants of uncertain significance, Br. J. Surg. 102 (11) (2015 Oct) 1354–1359. [32] L.C. Hartmann, D.J. Schaid, J.E. Woods, T.P. Crotty, J.L. Myers, P.G. Arnold, et al., Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer, N. Engl. J. Med. 340 (2) (1999 Jan 14) 77–84. [33] A.-B. Skytte, D. Crüger, M. Gerster, A.-V. Laenkholm, C. Lang, K. Brøndum-Nielsen, et al., Breast cancer after bilateral risk-reducing mastectomy, Clin. Genet. 79 (5) (2011 May) 431–437. European Society of Breast Cancer Specialists recommendations for the management of young women with breast cancer, Eur J Cancer Oxf Engl 48 (18) (1990) 3355–3377 2012 Dec. German Consortium for hereditary breast and ovarian cancer, [Internet]. [cited 2017 Dec 2]. Available from: http://www.konsortium-familiaerer-brustkrebs.de/. R.K. Schmutzler, K. Rhiem, P. Breuer, E. Wardelmann, M. Lehnert, S. 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Menke-Pluymers, C.C. Bartels, L.C. Verhoog, A.M. van den Ouweland, M.F. Niermeijer, C.T. Brekelmans, J.G. Klijn, Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation, N. Engl. J. Med. 345 (3) (2001 Jul 19) 159–164. F.E. Barton, J.M. English, W.B. Kingsley, M. Fietz, Glandular excision in total glandular mastectomy and modified radical mastectomy: a comparison, Plast. Reconstr. Surg. 88 (3) (1991 Sep) 389–392 discussion 393-394. M. Tewari, K. Kumar, M. Kumar, H.S. Shukla, Residual breast tissue in the skin flaps 133 The Breast 39 (2018) 8e13 Contents lists available at ScienceDirect The Breast journal homepage: www.elsevier.com/brst Original article Nipple-sparing bilateral prophylactic mastectomy and immediate reconstruction with TiLoop® Bra mesh in BRCA1/2 mutation carriers: A prospective study of long-term and patient reported outcomes using the BREAST-Q D. Casella a, G. Di Taranto b, *, M. Marcasciano a, b, S. Sordi c, A. Kothari d, T. Kovacs d, F. Lo Torto b, E. Cigna e, D. Ribuffo b, C. Calabrese c, d a Department of Oncologic and Reconstructive Breast Surgery, “Breast Unit Integrata di Livorno, Cecina, Piombino, Elba, Azienda USL Toscana Nord Ovest”, Italy b Plastic Surgery Unit, Department of Surgery “P. Valdoni”, Sapienza University, Rome, Italy c Oncologic and Reconstructive Surgery Breast Unit, Oncology Department, Careggi University Hospital, Florence, Italy d Breast Surgery Unit, Guy's Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, UK e Plastic and Reconstructive Surgery Unit, Hospital of Pisa, Italy a r t i c l e i n f o a b s t r a c t Article history: Received 7 August 2017 Received in revised form 19 December 2017 Accepted 6 February 2018 Available online 18 February 2018 Background: Although demand for prophylactic mastectomy is increasing over time among women at a high risk for breast cancer, there is a paucity of studies on long term patient-reported outcomes after this procedure. Methods: Between January 2011 and January 2015, 46 patients documented BRCA1/2 mutation carriers, eligible for prophylactic nipple-sparing mastectomy (NSM) and immediate breast prosthetic reconstruction were registered at our Institution. Patients underwent NSM and subcutaneous reconstruction with implant covered by a titanium-coated polypropylene mesh (TiLoop®). The BREAST-Q questionnaire was given to patients prior to surgery and at 1 and 2 years follow-up points. Capsular contracture was evaluated by Baker scale. Surgical outcomes along with the changes in BREAST-Q score were analyzed over time. Results: Complications were reported in only one case and after two years the capsular contracture rates were acceptable (grade I: 65,2%; grade II: 32,6%; grade III 2,2%). At one year and two year follow-ups patients reported high rates in the measures of overall satisfaction with breasts (72,5 and 73,7 respectively), psychosocial well-being (78,4 and 78,6), sexual well-being (58,8 and 59,4), physical well-being (77,6 and 80,6) and overall satisfaction with outcome (75,7 and 79,7). A statistically significant increase in all BREAST-domains from the preoperative to the postoperative period was reported at one and two years follow-ups (p < 0,05). Conclusion: Following bilateral prophylactic NSM and immediate subcutaneous reconstruction with TiLoop®, patients demonstrated high levels of satisfaction and quality of life as measured by BREAST-Q. 2-years outcomes confirmed high patient comfort with increased scores from the preoperative baseline level. © 2018 Elsevier Ltd. All rights reserved. Keywords: Nipple-sparing mastectomy (NSM) Prophylactic mastectomy TiLoop BRCA mutation Subcutaneous breast reconstruction 1. Introduction Considerable efforts have been made over the past decades * Corresponding author. Via dei Campani, 26, 00185 Rome, Italy. E-mail address: giuseppe.ditaranto@uniroma1.it (G. Di Taranto). https://doi.org/10.1016/j.breast.2018.02.001 0960-9776/© 2018 Elsevier Ltd. All rights reserved. toward the development of surgical management of breast cancer [1,2]. Surgical targets have rapidly evolved, aiming to optimize cosmetic outcomes and reduce patient morbidity, while still providing an oncologically-safe surgical procedure [3e6]. Surgeons moved from the radical mastectomy to the acceptance of breast conservation and aesthetic outcomes improvement as the achievable goals of surgical procedures. Skin sparing mastectomy (SSM) D. Casella et al. / The Breast 39 (2018) 8e13 and Nipple sparing mastectomy (NSM) have low local recurrence rates, comparable with total mastectomy and allows for immediate breast reconstruction [2]. Several studies revealed similar survival outcomes for NSM patients compared to SSM patients in the cancer setting and NSM has also shown favorable outcomes for risk reduction (RR) surgery [3]. Though NSM has been validated as an oncologically safe option, there are still some concerns regarding the risk of tumor recurrence in patients at the highest risk of breast cancer, such as BRCA1/2 mutation carriers [3]. It is reported that the risk of developing breast cancer in women with a BRCA1/2 mutation is of between 60 and 80% and that prophylactic mastectomy reduce the risk of breast cancer by up to 95% [7e9]. Due to the lack of long-term outcomes data in literature, the adoption of NSM in this patient population remains a subject of controversy. A recent study on 201 BRCA1/2 mutation carriers reported that NSM is associated with a low rate of complications and risk of breast cancer, comparable with SSM [3]. Although there is a growing body of evidence on oncologic and surgical safety of NSM, in this group of women, there is a paucity of studies on patient-reported outcomes. Few studies have examined the impact of nipple preservation, following nipple sparing prophylactic mastectomy (NSPM) and immediate breast reconstruction on health-related quality of life (HRQOL) [4e6,8e10]. Previous evaluations of patient outcomes after NSM have shown high levels of satisfaction, but these studies have all been somewhat limited by their retrospective design and heterogeneous or small sample size populations. The increased demand for NSM highlight the need for objective evaluation of HRQOL outcomes [11,12]. The aim of this study was to determine whether NSM, with immediate breast reconstruction using silicone implants and TiLoop® Bra mesh, could be established as a safe procedure and examine how HRQOL is influenced by nipple-areola complex preservation in a BRCA1/2 mutation carrier population. We prospectively evaluated the HRQOL using the BREAST-Q, a validated patient-reported outcome instrument developed specifically for patients undergoing breast reconstruction. 2. Materials and methods 2.1. Patients Between January 2011 and January 2015, patients with proven BRCA1 or BRCA2 gene mutation, undergoing prophylactic bilateral mastectomy at our institution, Azienda Ospedaliero-Universitaria Careggi, were enrolled for this study. These women, wanted and were suitable for nipple-sparing mastectomy and immediate breast prosthetic reconstruction; patients with “variants of uncertain significance” BRCA1/2 gene mutations were excluded. Inclusion criteria were documented BRCA1/2 mutation, body mass index (BMI) between 25 and 35 kg/m2, no previous breast surgery, no evidence of cancer on clinical examination or imaging (magnetic resonance imaging (MRI), mammogram and ultrasound) and suitability for immediate reconstruction with subcutaneous implants. Prior to surgery, all patients were evaluated for both autologous or alloplastic breast reconstruction, taking into account patient preference, body habitus, co-morbidities and prior abdominal surgery. We enrolled in this study only patients willing to undergo prosthetic breast reconstruction, who refused autologous reconstruction or presenting any contraindication to these procedures. This study was approved by our institutional Ethics Committee and all patients provided written informed consent. 2.2. Operative technique We have previously published our surgical technique for NSM 9 and immediate reconstruction with implant and TiLoop® Bra mesh [13e15]. Briefly, the mastectomy was performed through an inframammary or lateral incision and skin flaps were raised in the subdermal plane. Once the breast tissue had been resected, the nipple tissue was cored out, while preserving the NAC skin. The excised tissue along with a specimen of the tissue underlying the NAC was sent to the pathologist for definitive histological evaluation. Patients underwent immediate reconstruction through definitive implant placement using a titanium-coated polypropylene mesh (TCPM), specifically TiLoop® Bra (TiLOOP® Bra, pfm medical, Cologne, Germany). The skin flaps were assessed and when considered adequate, after confirming definitive implant with a sizer, a TiLoop® Bra mesh bag was adjusted around the implant. Using absorbable sutures, a TiLoop® sheet was folded onto itself to create a bag which eventually functioned as a pocket for the breast implant. In the case of larger implants, two TCPM sheets were used and stitched together. The TCPM bag, with the implant inside, was then placed in a totally subcutaneous pre-pectoral position. Medial and lateral borders were secured to the muscular fascia with interrupted absorbable sutures. One vacuum drain was inserted in the inframammary fold and patients received oral antibiotics until surgical drains were removed. Patients were evaluated every two weeks for the first 2 months and follow-up visits were performed every 2 months thereafter. All the procedures were performed by the same surgeons. 2.3. Outcomes and measures A secure digital database was prospectively created in order to collect data on patient demographics, BRCA mutation, medical history, family history, surgical complications and capsular contracture. Surgical complications were named as implant removal, skin-nipple necrosis, seroma, wound dehiscence, surgical site infection and hematoma. HRQOL and cosmetic outcome evaluation were conducted using the preoperative and the postoperative BREAST-Q modules for reconstructive surgery [16e24]. Enrolled patients received the preoperative questionnaire from the BREAST-Q reconstructive module after consultation with both the surgical oncologist and the plastic surgeon one month before the mastectomy. Patients were required to answer The BREAST-Q postoperative module at 1 and 2 years after mastectomy. At these time points, surveys were given directly to patients during their scheduled clinic visit. All aspects of the BREAST-Q reconstructive module (Satisfaction with Breasts, Satisfaction with Outcome, Psychosocial Well-being, Physical Well-being and Sexual Wellbeing) were included with exception of questions regarding abdominal donor site. In keeping with the developers' guidance, patients who failed to answer more than half the items within each domain were excluded from the analysis for that particular domain [16,23,24]. Baker Scale was used for scoring capsular contracture during postoperative follow-ups, at one and two years after mastectomy. The completed questionnaires were reviewed by the senior authors (RD, CE) and our co-authors from the Breast Unit of Guy's Hospital, London. 2.4. Statistical analysis Descriptive statistic accounted for patient sociodemographic, clinical characteristics, complications and capsular contracture grade. Using the QScore Scoring Software, BREAST-Q scores were converted from survey raw scores (1 through 4 or 5) to a continuous range from 0 to 100, with a higher score representing greater satisfaction or better HRQOL. The scores for each BREAST-Q matrix indexes were determined at each time point and then entered into 10 D. Casella et al. / The Breast 39 (2018) 8e13 the database, along with the other data collected from patients and medical records. Both absolute BREAST-Q scores and changes in scores before and after treatment were analyzed. The Shapiro-Wilk test was used to verify for normal distribution of continuous variables. Consequently, Breast-Q scores were analyzed using Student t-distribution. P values less than 0.05 were considered statistically significant. 3. Results 3.1. Patient characteristics A total of 46 women BRCA1/2 mutation carriers were enrolled in to this study. Table 1 describes the demographic characteristics of participants. The 91,3% of the patients was Caucasian and the mean age at the time of NSPM was 43,2 years (range 23e65 years). The mean BMI was 28,4 kg/m2 (range 25e35 kg/m2). The mean time interval from patients' mutation diagnosis to surgery was 7.3 months (range 4e14 months). The drain was removed between the fourth and ninth postoperative day (mean value: 6,5 days). Complications were recorded in 1 patient, who developed necrosis of the breast skin flaps that required explantation. She underwent revision reconstruction using sub-pectoral expanders, followed by second stage replacement of the expander by definitive breast implant and lipofilling after 6 month. There were no cases of NAC necrosis and one patient had positive histological evaluation at the definitive analysis. Incidental stage 0, non invasive breast cancer was found in 1 patient. We did not detect any cases of severe capsular contracture (grade IV) at both follow-up points and, after two years, 30 patients were evaluated as grade I (65,2%), 15 patients as grade II (32,6%) and 1 patients grade III (2,2%). After one year in 7 cases an additional intervention in the form of lipofilling was required for either, visible implant creasing or implant edge palpability [25,26]. The mean volume of injected fat was 20,3 ml per breast. A one year follow-up clinic visit was scheduled in all cases before a second operation (Figs. 1 and 2). 3.2. Measure of HRQOL All patients adequately answered for the five domains of the questionnaire. Tables 2 and 3 show the self-reported measures of Table 1 Demographic characteristics. Patient characteristic All patient (46) Age [years, mean (range)] BMI [kg/m2, mean (range)] Ethnicity (n, %) Caucasian Hispanic Asian Marital status (n, %) Married Divorced Separated Single Comorbidities (n, %) Diabetes Connective tissue diseases Smoking (n, %) Never smoker Past smoker Active smoker BRCA Mutation (n, %) BRCA1 RCA2 43,2 (23e65) 28,4 (25e35) 42 (91,3) 2 (4,3) 2 (4,3) 27 (58,7) 4 (8,7) 2 (4,3) 13 (28,3) 3 (6,5) 1 (2,1) 28 (60,9) 10 (21,7) 8 (17,4) 30 (6,52) 16 (34,8) HRQOL, evaluated with BREAST-Q questionnaire, at the preoperative setting compared to 1 year and 2 years respectively, after reconstruction. Significant increases from the base line were reported in the domains for overall satisfaction with breasts (p < 0,05), psychosocial well-being (p < 0,05) and sexual well-being (p < 0,05) at both follow-ups. The scores tended to improve overtime at the second follow-up. The measure for physical impact of the surgery declined from the preoperative to postoperative evaluations, but this was not observed to be statically significant. Overall satisfaction with outcome index, measured postoperatively, was higher and improved over time throughout the post-operative period, but this was not significant (p ¼ 0,091). 4. Discussion Consequent to extensive coverage by the media there is an enhanced awareness amongst women about hereditary breast cancer. Newer testing guidelines and patient choice has led to an increase in BRCA mutation testing and genetic counseling, allowing patients to consciously consider prevention and therapy-related complications, while making decisions about surgical management of breast cancer [27e31]. The number of women seeking gene testing continues to rise and in Italy some medical societies are claiming implementation of specific health pathways, targeting toward early diagnosis and reduction of BRCA-related cancer risk rate [32]. Italian press named “right of gene” the request of introducing BRCA mutations screening among the basic healthcare services the national health system provides by law. For women at highest risk for breast cancer, risk-reducing surgery has been associated with the greatest potential benefit in terms of decreasing the chance of developing breast cancer and demand for prophylactic mastectomy is increasing over time amongst this cohort of women [3]. In this regard, the value of a spared NAC for women psychological and sexual functions has been described before. However, little is known about the impact of these risk-reducing strategies on quality of life, and more research is needed in order to achieve robust and sound scientific evidence [3e8]. Our prospective study looks at the immediate and long term surgical and BREAST-Q outcomes for a series of 46 patients who underwent NSM and immediate reconstruction with TiLoop® Bra mesh. Our data demonstrates the safety and reliability of this technique, reporting satisfactory long term results with low complication rates and high patient satisfaction. 2-year outcomes for quality of life confirm high patient satisfaction following prophylactic mastectomy and suggest that NSM and TiLoop® immediate pre-pectoral breast reconstruction has the potential for providing a valid and safe aesthetic alternative. Furthermore, 2 years following surgery, patients reported significantly high scores in the self-reported measures of overall satisfaction with breasts (73,7), psychosocial well-being (78,6) and sexual well-being (59,4). The patients demonstrated a significant increase in self-reported measures from the preoperative to the postoperative period at one and two years follow-ups. All the postoperative data were evaluated both in absolute terms and in relation to preoperative results, as changes in scores were considered a more reliable and comparable measurement. Indeed, recently Howard et al. prompted to define the precise “minimally important differences” for BREAST-Q scores and proposed new baseline scores for BREAST-Q results in NSM surgery [5]. This study prospectively analyzed a heterogeneous population of 39 patients undergoing NSM for cancer treatment (n ¼ 17) or (Risk Reducing) RR (n ¼ 22) and immediate 1- and 2-stage implant or autologous immediate breast reconstruction and demonstrated high levels of satisfaction and quality of life as measured by BREAST-Q [5]. Another prospective D. Casella et al. / The Breast 39 (2018) 8e13 11 Fig. 1. A 42-year-old woman who underwent bilateral prophylactic NSM (inframammary fold incision) and direct-to-implant reconstruction: preoperative (left) and 2 year's postoperative (right). Fig. 2. A 38-year-old woman who underwent bilateral prophylactic NSM (lateral incision) and direct-to-implant reconstruction: preoperative (left) and 3 months' postoperative (right). study designed by Peled at al, reported preoperative and one year follow-up outcomes of 28 NSM patients undergoing RR or cancer treating mastectomy and expander-implant reconstruction, evaluated with the BREAST-Q [4]. Other studies adopted BREAST-Q questionnaire for evaluating patients following NSM, but this was collected retrospectively and almost all the authors applied only the postoperative modules [6,10,21,22,33]. Furthermore as populations of these studies encompass woman with different characteristics, undergoing mastectomy for either therapeutic or prophylactic reasons and reconstruction with several techniques, it would be incongruous comparing our results with the measures provided by other authors. As postulated by Howard, preoperative measurements of breast health, psychosocial well-being, and sexuality establish a baseline measurement with which to determine if surgery decreases or increases these quality of life outcomes [5]. We agree that without a baseline measurement it is impossible to know if a score, even if high or at a long term follow-up after surgery, is actually a change from the baseline score. Nevertheless, our scores correlated well with the data from Howard's study, regarding only the small cohort of patients (n ¼ 22) undergoing RR mastectomy [5]. Interestingly, as previously reported by other studies, we found in our clinical practice that RR and cancer patients who apply BREAST-Q questionnaire routinely at our institution scored relatively similar preoperative values (data not shown) [4,5]. It is possible that a new diagnosis of BRCA1 or 2- gene mutation would have a similar negative psychological impact as a cancer diagnosis in our patients series. Following this hypothesis, patients at high risk for breast cancer behave as they feel carriers of a disease rather than a simple gene mutation, affecting their psychological status and social life. However, RR patients scored high BREAST-Q results at 1-year and 2-years follow-up and expressed great overall satisfaction with outcome. We mainly ascribe these results to the relief experimented by patients after breast removal due to the decreased Table 2 BREAST-Q scores recorded preoperatively and one year postoperatively, expressed as mean ± standard deviation. Changes in scores are expressed as delta (postoperative score minus preoperative score). *P < 0,05. Domain Preoperative mean (±SD) Postoperative mean (±SD) Delta mean p-value Satisfaction-breasts Psychosocial wellness Sexual well-being Physical impact (chest) Overall satisfaction with outcome 59,3 66,4 52,7 80,9 e 72,5 78,4 58,8 77,6 75,7 13,2 12 6,1 3.3 e 0.0033* 0.0132* 0.0253* 0.0984 e (±12,2) (±13,7) (±14,4) (±10,4) (±10,1) (±13,3) (±12,6) (±14,2) (±12,3) 12 D. Casella et al. / The Breast 39 (2018) 8e13 Table 3 BREAST-Q scores recorded preoperatively and two year postoperatively, expressed as mean ± standard deviation. Changes in scores are expressed as delta (postoperative score minus preoperative score). *P < 0,05. Domain Preoperative mean (±SD) Postoperative mean (±SD) Delta mean p-value Satisfaction-breasts Psychosocial wellness Sexual well-being Physical impact (chest) Overall satisfaction with outcome 59,3 66,4 52,7 80,9 e 73,7 78,6 59,4 80,6 79,7 14,4 12,2 6,7 0,3 e 0.0145* 0.0193* 0.0179* 0.0846 e (±12,2) (±13,7) (±14,4) (±10,4) likelihood of developing a breast cancer rather than to the simple breast aesthetic outcome. Indeed, in our study only three patients required a breast augmentation, while the others were satisfied with their breast shape and volume and did not ask for an augmentation. We believe that the reported increased scores could result as a merge of both the reduced risk of breast cancer concerning the patients and the acceptable aesthetic result provided by the subcutaneous reconstruction. NSM and immediate breast reconstruction offers a safe option, providing a fast recovery and an appealing alternative from both an aesthetic and psychological point of view, improving cosmesis following mastectomy. In our opinion, among different reconstructive techniques, immediate one-stage reconstruction is a valid choice for preserving women's quality of life after mastectomy. In particular subcutaneous prosthetic reconstruction with TiLoop® Bra mesh guarantees higher levels of patient-reported outcomes [13e15]. The main advantages of this technique are the preservation of the pectoralis major muscle with reduced or absent muscular pain and a comparable rate of other minor complications, less invasiveness, reduction of surgical times (one-stage technique), early discharge and rapid recovery [13e15]. Furthermore in our study, we reported low complication rates. Comparing to cancer treating surgery, this good rate could be ascribed to several factors. First, our patients are mutation carriers undergoing prophylactic bilateral mastectomy for risk reducing purpose. Therefore, they did not undergo any chemotherapy or radiotherapy, which have been associated to an increased rate of postoperative complication, such as delayed healing, wound dehiscence, skin flaps and nipple necrosis and severe capsular contracture [27,28,34,35]. Another possible explanation of the low complications rate could rely on our subcutaneous reconstructive technique [34]. Indeed, it requires short intraoperative time. Tiloop does not require any rehydration or long treatment before use with an estimated setting time as low as 3e5 min, reducing the intraoperative time of exposure of the implant and the mesh, along with the possibility of intraoperative contamination and infections. Nevertheless, we consider that our follow-up is short for drawing conclusion in the setting of capsular contracture and other implant-related complications; we believe that our complications rate could increase over time and we strictly follow up patients for contracture evaluation. To our knowledge, this is the first study prospectively evaluating long-term outcomes after bilateral NSM and immediate breast reconstruction in a population of BRCA1/2 mutation carriers, applying BREAST-Q questionnaire to preoperative and postoperative points and analyzing scores and their changes over time. Indeed patients showed high levels of overall satisfaction with outcome and wellness. We believe that our data could help clinicians in counseling women at high risk for breast cancer and provide patients with reliable outcomes after prophylactic mastectomy. Acknowledgments and conflict of interest The authors have no commercial, proprietary, or financial (±9,8) (±13,7) (±13,5) (±13,6) (±11,8) interest in the products or companies described in this article. Our study was performed with respect to the ethical standards of the Declaration of Helsinki, as revised in Tokyo 2004. The study complies with the policy of the journal on ethical consent. References [1] de Alcantara Filho P, Capko D, Barry JM, Morrow M, Pusic A, Sacchini VS. Nipple-sparing mastectomy for breast cancer and risk-reducing surgery: the Memorial Sloan-Kettering Cancer Center experience. Ann Surg Oncol 2011 Oct;18(11):3117e22. [2] De La Cruz L, Moody AM, Tappy EE, et al. Overall survival, disease-free survival, local recurrence, and nipple-areolar recurrence in the setting of nipplesparing mastectomy: a meta-analysis and systematic review. Ann Surg Oncol 2015;22:3241e9. [3] Yao K, Liederbach E, Tang R, Lei L, Czechura T, Sisco M, et al. Nipple-sparing mastectomy in BRCA1/2 mutation carriers: an interim analysis and review of the literature. Ann Surg Oncol 2015 Feb;22(2):370e6. [4] Peled AW, Duralde E, Foster RD, Fiscalini AS, Esserman LJ, Hwang ES, Sbitany H. Patient-reported outcomes and satisfaction after total skin-sparing mastectomy and immediate expander-implant reconstruction. Ann Plast Surg 2014 May;72(Suppl 1):S48e52. [5] Howard MA, Sisco M, Yao K, Winchester DJ, Barrera E, Warner J, et al. Patient satisfaction with nipple-sparing mastectomy: a prospective study of patient reported outcomes using the BREAST-Q. J Surg Oncol 2016 Sep;114(4): 416e22. [6] Metcalfe KA, Cil TD, Semple JL, Li LD, Bagher S, Zhong T, et al. Long-term psychosocial functioning in women with bilateral prophylactic mastectomy: does preservation of the nipple-areolar complex make a difference? Ann Surg Oncol 2015 Oct;22(10):3324e30. [7] Wagner JL, Fearmonti R, Hunt KK, Hwang RF, Meric-Bernstam F, Kuerer HM, et al. 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Research Article Breast Care 2019;14:217–223 DOI: 10.1159/000496398 Published online: February 15, 2019 Patient-Reported Satisfaction after Prophylactic Operations of the Breast Katja Keller a, b, c Cornelia Meisel a, b, c Nannette Grübling a, b, c Andrea Petzold a, b, c Pauline Wimberger a, b, c Karin Kast a, b, c a Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, b National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, and c German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany Keywords Prophylactic mastectomy · Satisfaction · BRCA1/BRCA2 mutations · Long-term follow-up · Breast cancer Abstract Background: Prophylactic mastectomies in carriers of mutations in BRCA1 or BRCA2 are becoming increasingly more accepted. We investigated the outcome after prophylactic mastectomy, especially regarding satisfaction with the procedure, in a monocenter study. Methods: BRCA1/2 mutation carriers and non-carriers with elevated pedigree-based cancer risk were followed prospectively in a structured surveillance program between 2000 and 2017. A retrospective telephone survey was conducted among all patients with documented prophylactic mastectomy. Complications and satisfaction with the decision for prophylactic mastectomy were recorded. Results: 39 patients who opted for a prophylactic mastectomy (38 BRCA1/2 mutation carriers and 1 noncarrier) were interviewed. Mostly nipple-sparing mastectomy with reconstruction was performed (87%). Half of the patients (22/39; 56.4%) had a history of unilateral breast cancer. The median time since prophylactic mastectomy was 5.6 years. While 61.5% did not report any complications, flap loss was seen in 15% (3/20) and moderate limitations in everyday life were present in 20% (7/35). An improvement in quality of life was noticed by 82% after prophylactic mastectomy and no patient expressed regret with regard to the decision. Conclusions: Prophylactic mastectomy is a procedure with © 2019 S. Karger AG, Basel E-Mail karger@karger.com www.karger.com/brc risk for long-term complications in some cases. Our results confirm high satisfaction with the decision and improved quality of life. © 2019 S. Karger AG, Basel Introduction BRCA1/2 mutation carriers face a high lifelong risk for breast and ovarian cancer. For both genes, the breast cancer risk until the age of 80 years is 70%, and for ovarian cancer it is 40% and 17% for BRCA1 and BRCA2, respectively [1]. Intensified screening programs with breast magnetic resonance imaging (MRI) aim to improve the prognosis of breast cancers through early detection, and there is evidence for a survival benefit by surveillance [2]. But mutation carriers increasingly opt for risk-reducing operations of the breast. For healthy carriers, not only a reduction of 90–95% in the risk of subsequent breast cancer was shown by bilateral prophylactic mastectomy, but also improved overall survival was described [3]. In patients with unilateral breast cancer, the benefit of contralateral prophylactic mastectomy is less clear [4, 5]. Prior to the risk-reducing surgery, comprehensive counseling at different time points is necessary. Counseling should take place in specialized centers and should contain different reconstruction methods, such as the use of implants and autologous tissue. The decision is guided by a woman’s activity and plans, body shape, and personal preferences. Karin Kast, MD Carl Gustav Carus University Dresden, Technische Universität, University Hospital Dresden, Fetscherstraße 74 DE–01307 Dresden (Germany) E-Mail karin.kast @ universitätsklinikum-dresden.de Table 1. Questionnaire for the telephone interview Questions Spectrum of answers Type of mastectomy Type of reconstruction Number of operations Complications after surgery Satisfaction with cosmetic result Pain Improvement of quality of life Limitations in everyday life Limitations in leisure time and activities Same decision for prophylactic surgery again? Negative impact on family/partnership? Salpingo-oophorectomy MRM none total none not at all none none none none yes yes yes SM implant moderate rather unsatisfied little little little little no no no autologous tissue severe indifferent moderate moderate moderate moderate different indifferent satisfied strong severe severe severe very satisfied severe MRM, modified radical mastectomy; SM, subcutaneous mastectomy. Satisfaction of patients depends on the esthetic outcome, freedom from lasting symptoms with limitations in daily life, and reduction of anxiety after surgery. According to 1 meta-analysis, most patients would decide to have the same procedure performed again [5]. But after unilateral sporadic breast cancer, reduced satisfaction of patients with contralateral prophylactic mastectomy with one or more unplanned following surgeries was described [6]. In addition, more body image problems and less sexual pleasure, but less anxiety and improved social activities were reported in a study of women with familial risk for breast cancer at 1 year after prophylactic bilateral breast cancer [7]. With this study, we aimed to investigate the complication rate and satisfaction of carriers at the Dresden center of the German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC) after prophylactic operations of the breast with and without prior breast cancer diagnosis. Methods Between 2000 and 08/2017, all patients who fulfilled certain criteria of familial cancer risk were counseled interdisciplinarily, and molecular genetic analysis was carried out as described previously at the Dresden center of the GC-HBOC [8]. Prophylactic risk-reducing operations were offered to all women with a pathologic mutation in BRCA1 or BRCA2. After consenting to participate in the study, each family was documented in the mutual database of the GC-HBOC. Follow-up was performed for all women who took part in our center’s intensified surveillance program or by personal contact with carriers and individuals with very high pedigree-based risk who sought additional counseling for prophylactic operations. All women after risk-reducing bilateral mastectomy are offered to undergo one last MRI to rule out remaining breast tissue in order to objectify the surgical outcome under research conditions 1 year after the procedure. Between 04/2017 and 08/2017, a telephone survey was conducted among all patients with a documented history of prophy- 218 Breast Care 2019;14:217–223 DOI: 10.1159/000496398 lactic surgery of the breast in our database. Altogether, 44 women were eligible, of whom 39 were interviewed by a breast surgeon and 5 were lost to follow-up. The interview consisted of 18 questions on type of surgery, status of reconstruction, early and late complications, and number of operations (table 1). Moreover, satisfaction, limitations in daily life, and extent of anxiety reduction were enquired about (table 1). The data cut of the database was 08/2017. Statistical analyses were performed with SPSS. Results Altogether, 1,319 families were counseled at the Dresden center, with 330 families carrying a pathogenic mutation in BRCA1 or BRCA2, of which roughly 11% of the women at risk opted for a prophylactic mastectomy. Of the 39 patients with documented prophylactic mastectomy and a telephone interview, 38 were carriers of a pathogenic mutation. 1 patient with prophylactic mastectomy without BRCA1/2 mutation was from a family with very high pedigree-based risks. The median age at the time of the interview was 47 years. The median time since breast cancer in affected individuals was 7.8 years and the median time since prophylactic mastectomy was 5.6 years. The characteristics of the participants of the telephone interview are displayed in table 2. In 43.6% (17/39) of the women, an exclusively prophylactic operation was performed (bilateral mastectomy in a healthy individual). About half of the patients (22/39; 56.4%) were affected with unilateral breast cancer (table 3), some of whom had a primary mastectomy, e.g. after neoadjuvant chemotherapy, while others opted for a secondary bilateral mastectomy after initial breast-conserving surgery (table 2). Of the 39 patients under investigation, 25 (64.1%) reported having undertaken a bilateral prophylactic salpingo-oophorectomy (table 2). Keller/Meisel/Grübling/Petzold/ Wimberger/Kast Table 2. Characteristics of the participants in the telephone interview Characteristics n Value Participants, all Healthy mutation carrier Healthy without BRCA1/2 mutation Patients with unilateral breast cancer Age at time of interview, years, median (range) Time since breast cancer, years, median (range) Time since prophylactic mastectomy, years, median (range) Prophylactic salpingo-oophorectomy, yes/no Prior chemotherapy, yes/no Prior radiation therapy, yes/no 39 17 1 21 39 21 39 39 21 21 47 (26‒75) 7.8 (3‒33) 5.6 (1‒32) 24/15 17/4 5/16 Most of the patients with bilateral mastectomy were treated with nipple-sparing subcutaneous mastectomy (34/39; 85%) and alloplastic or autologous reconstruction, while some wished to receive a modified bilateral mastectomy (10%) without reconstruction (fig. 1a). All of the latter were unilaterally affected carriers of mutations in BRCA1 or BRCA2. Of the 35 patients with reconstruction, 43% (15/35) opted for breast implants, while 57% (20/35) were reconstructed with autologous tissue (fig. 1b). Reconstruction with implants was mostly performed during a single surgery (12/15; 80%). 2 patients needed 2 different surgeries and 1 patient had her implants successfully placed only after 4 surgeries, due to wound healing problems. For autologous reconstruction, a median of 3 surgeries were necessary. Only 4 out of 20 patients (20%) with autologous reconstruction had their surgery completed within a single operation. Reconstruction was performed without any complications in 61.5% (24/39) of the patients and moderate complication such as infection or rebleeding occurred in 11 patients (11/39; 28.2%). 3 women (7.7%) faced severe complications: 2 with loss of the transplanted tissue flap and 1 with loss of the breast implant (fig. 1d). No lifethreatening complications were observed. Most patients were satisfied or very satisfied with the cosmetic outcome of their prophylactic mastectomy at the time of the interview (33/39; 85%). Only 4 reported discontent (4/39; 10%) with the cosmetic outcome and 2 (2/39; 5.1%) would elect a different type of operation. For example, one of these patients would prefer a subcutaneous rather than a subpectoral location for her implant. Patients with autologous reconstruction displayed higher satisfaction with the result (19/20; 95%) compared to those operated with implant reconstruction (11/15; 73.3%). Moreover, patients after unilateral breast cancer were more often satisfied with the result (16/18; 88.9%) than healthy carriers (14/17; 82.4%). In terms of long-term surgery-associated morbidity, 59% (23/39) of the patients had no pain. Severe pain was not reported by any of the patients. About half of the pa- Table 3. Tumor characteristics Satisfaction after Prophylactic Operation Breast Care 2019;14:217–223 DOI: 10.1159/000496398 n Size of tumor Tis T1 T2 T3/T4 Unknown 1 13 6 0 2 Total 22 Nodal status N0 N1 Unknown 13 6 2 Total 21 Metastases M0 M1 Unknown 22 0 0 Total 22 Tumor biology HR+, HER2– HR–, HER2– HR–, HER2+ HR+, HER2+ Unknown 6 12 1 1 2 Total 22 HR, hormone receptor; HER2, human epidermal growth factor receptor 2. tients experienced no limitations in everyday life (20/39; 51.3%) or in the selection of their recreational activities or hobbies (25/39; 64.1%). Severe limitations were not reported by any patient, moderate limitations in everyday life were reported by 7 patients (7/39; 18%), and moderate limitations in leisure time activities by 4 (4/39; 10.3%) (fig. 1e). A moderate restriction in everyday life was, for example, that it was no longer possible to lift or carry 219 a b Type of mastectomy Type of reconstrucƟon 10% 10% subcutaneous mastectomy 90% d 38% moderate complicaƟons 63% severe compliĐĂƟons no e f Decision for prophylacƟc surgery LimitaƟŽŶƐ 30 25 20 20 0 without complicaƟŽŶƐ 24% yes - fewer 10 ComplicaƟons 13% yes - moderate 24% reconstrucƟon with breast implants reconstrucƟon with autologous ƟƐƐue yes - very 16% 22% 39% modiĮed bilateral mastectomy Improvement of quality of life c 51% without reconstrucƟon 7 10 0 0 limŝƚĂƟon everyday life very yes again 5% 12 moderate no diīerent 4 no not at all limŝƚĂƟon leisure and hobbies fewer 95% no Fig. 1. Results of the telephone interview. a Type of mastectomy, b type of reconstruction, c improvement of quality of life, d Complications, e Limitation in everyday life/leisure time activities, f decision for prophylactic surgery. heavy weight, and in leisure time activities that a prone position was no longer possible. Improvement in quality of life was seen in 78% of patients, with reduction of anxiety being the most important reason (fig. 1c). While 95% of the patients would opt for the same procedure again, 5.1% would choose another type of surgery. None of the 39 individuals under investigation reported regrets in terms of their decision for prophylactic mastectomy (fig. 1f). One of the patients had a local recurrence, but none developed metastatic disease. Discussion We searched our database for women with documented prophylactic mastectomy after interdisciplinary counseling and molecular genetic analysis of the breast cancer genes in our GC-HBOC center in Dresden. With about 11%, the percentage of carriers who decided to undergo prophylactic mastectomy was low. About half of them had a history of breast cancer, although overall survival benefit has primarily been shown in healthy carriers. In the past, differences in uptake of prophylactic mastectomy were reported among different cultures. Compared to more conservative countries such as France and Poland, uptake in countries such as the USA, Sweden or The 220 Breast Care 2019;14:217–223 DOI: 10.1159/000496398 Netherlands was higher [9–12]. With the outing of Angelina Jolie in 2013, the procedure lost its taboo, and we noticed an increase in requests for the surgery at our center. Only recently did another center of the GC-HBOC report a higher rate of prophylactic mastectomy, namely 27% and 44% among affected and healthy BRCA1/2 mutation carriers, respectively [13]. This difference might be mainly explained by the different approach they adopted in their study. Schott et al. [13] sent questionnaires to all patients who were counseled at the center in Heidelberg, whereas we recorded operations that were actively communicated. However, cultural reasons cannot be completely excluded in comparing centers in the former western part of Germany with those in the former eastern part. Unplanned additional operations, wound healing problems, and flap loss were described as negative side effects in the meta-analysis of Lostumbo et al. [5]. In a recent one-center study, the overall complication rate was reported to lie at 15.9%, with significantly less complications after autologous reconstruction compared to alloplastic reconstruction [14]. Generally, wound infections and seromas are more common in alloplastic breast implants [14, 15]. Autologous reconstruction was reported to be associated with longer hospital stays, but also with fewer operations, less reconstruction failures Keller/Meisel/Grübling/Petzold/ Wimberger/Kast (7.3 vs. 1.3%) and a shorter time to full achievement of reconstruction [16–18]. Complication rates are higher after neoadjuvant chemotherapy or after radiation therapy in smoking or obese patients [19]. After alloplastic breast reconstruction, Mousa et al. [20] reported postoperative complications in 45% of patients, of which 29% occurred after prior neoadjuvant chemotherapy and 25% after prior radiotherapy. In 30% of patients, revisional surgery (closure of wound, debridement, exchange or removal of implant) was needed. In our cohort, the overall complication rate was 38%, which might be due to the high percentage of women participating in the study after treatment for prior breast cancer. With the exception of 2 women, all patients would elect the same procedure again. The number of severe complications such as flap loss after autologous reconstruction is rather high. The operations took place in different hospitals all over Germany. In order to guarantee high oncologic safety and the best possible aesthetic outcome with low complication rates, these complex operations should only be performed in centers with interdisciplinary teams of oncologic and plastic surgeons [21, 22]. But the patient’s wish is not regulated further, for instance by limited insurance coverage. In spite of complications, most women after prophylactic mastectomy reported high satisfaction with their decision in the meta-analysis of Lostumbo et al. [5]. This is in accordance with our findings. Even in cases of dissatisfaction with the cosmetic outcome, all our patients would opt to undergo the risk-reducing operation again. Satisfaction with cosmetic outcome was higher after autologous reconstruction, which is in accordance with the literature [17, 23–27]. But due to the small numbers in our analysis and differences in preconditions for the individual woman, this implies no general advice to prefer one method over the other. In our study, patients after unilateral breast cancer reported higher satisfaction compared to healthy patients. Although this was expected, one other group found partly different results. Kazzazi et al. [24] describe higher satisfaction among healthy individuals or after bilateral breast cancer with mastectomy and reconstruction compared to those with unilateral breast cancer with bilateral mastectomy and reconstruction. As an explanation, lack of time for making the decision for contralateral mastectomy is suggested. Most study participants reported improvement in quality of life primarily due to reduction of anxiety. Those with unchanged quality of life reported having taken a rational decision without feeling stressed by anxiety before the operation. With a mean follow-up time of 14.5 years, a retrospective study by Frost et al. [28] found satisfaction with the procedure in 70% of all patients. More- Satisfaction after Prophylactic Operation over, increase in emotional stability and decrease in stress was perceived in about 25% of patients. A number of smaller studies with a short follow-up of 1–2 years provide similar data [7, 28–31], but long-term prospective studies are still needed for the comprehensive counseling of patients at high risk for breast cancer. The strength of our analysis lies in the qualified telephone interview conducted by a breast surgeon. Especially for patients with prior unilateral breast cancer, it is sometimes challenging to answer questions on intention, number of surgeries, or type of complication. A limitation of our study is the restricted follow-up of the 1,319 families at our center. Not all families are represented with at least 1 participant in our intensified surveillance program. Therefore, underestimation of the rate of uptake of prophylactic mastectomies is possible. Moreover, our sample is too small to compare the impact of type of mastectomy and reconstruction on complications and quality of life. It should also be mentioned that no validated questionnaire was used to enquire about patient satisfaction. Prophylactic mastectomy is the most effective procedure to improve survival rates in healthy carriers of a mutation in BRCA1/2 and possibly also in unilaterally affected carriers. As we can confirm, psychosocial benefits outweigh possible early and late side effects of the surgery. Knowledge on genetic and non-genetic risk modifiers might help to define individual risk and the timing of the procedure in the future. Acknowledgements We thank Rita Schmutzler, Christoph Engel, and all investigators of the GC-HBOC for establishing the background on the basis of which this work was possible. At the center in Dresden, we especially thank Dominique Weise, Sylke Schmidtke, Kristin Eichhorn, and Nannette Kranz for their continuous commitment in patient management, documentation, and analysis. We thank Evelin Schröck, Andreas Rump, Karl Hackmann, Arne Jahn, and Johannes Wagner for genetic counseling and analysis. We thank all the patients for their individual contribution to this research. Finally, we thank the German Cancer Aid for their support of the GC-HBOC with grant no. 110837. Statement of Ethics The study protocol has been approved by the research institute’s committee on human research. Funding Sources German Cancer Aid grant no. 110837 for GC-HBOC. Breast Care 2019;14:217–223 DOI: 10.1159/000496398 221 Author Contributions Disclosure Statement K.Ke.: Conception of the work, analysis and interpretation of data, writing of the manuscript, final approval of the version to be published; C.M.: conception of the work, acquisition, interpretation of the data, final approval of the version to be published; K. Ka.: conception of the work, acquisition, interpretation of data, critical revision of the manuscript for important intellectual content, final approval of the version to be published; all other authors: acquisition of data, critical revision of the manuscript for important intellectual content, final approval of publication. The authors have no conflicts of interest to declare. References 1 Kuchenbaecker KB, Hopper JL, Barnes DR, et al: Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 2017;317:2402–2416. 2 Evans DG, Harkness EF, Howell A, Wilson M, Hurley E, Holmen MM, Tharmaratnam KU, Hagen AI, Lim Y, Maxwell AJ, Moller P: Intensive breast screening in BRCA2 mutation carriers is associated with reduced breast cancer specific and all cause mortality. Hered Cancer Clin Pract 2016;14:8. 3 Hartmann LC, Lindor NM: The role of riskreducing surgery in hereditary breast and ovarian cancer. N Engl J Med 2016; 374: 454– 468. 4 Heemskerk-Gerritsen BA, Rookus MA, Aalfs CM, Ausems MG, Collee JM, Jansen L, Kets CM, Keymeulen KB, Koppert LB, MeijersHeijboer HE, Mooij TM, Tollenaar RA, Vasen HF, Hooning MJ, Seynaeve C: Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis. Int J Cancer 2015; 136: 668–677. 5 Lostumbo L, Carbine N, Wallace J, Ezzo J: Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev 2004;(4):CD002748. 6 Boughey JC, Hoskin TL, Hartmann LC, Johnson JL, Jacobson SR, Degnim AC, Frost MH: Impact of reconstruction and reoperation on long-term patient-reported satisfaction after contralateral prophylactic mastectomy. Ann Surg Oncol 2015;22:401–408. 7 Brandberg Y, Sandelin K, Erikson S, Jurell G, Liljegren A, Lindblom A, Linden A, von Wachenfeldt A, Wickman M, Arver B: Psychological reactions, quality of life, and body image after bilateral prophylactic mastectomy in women at high risk for breast cancer: a prospective 1-year follow-up study. J Clin Oncol 2008;26:3943–3949. 8 Meisel C, Sadowski CE, Kohlstedt D, Keller K, Staritz F, Grubling N, Becker K, Mackenroth L, Rump A, Schrock E, Arnold N, Wimberger P, Kast K: Spectrum of genetic variants of BRCA1 and BRCA2 in a German single center study. Arch Gynecol Obstet 2017; 295: 1227– 1238. 222 9 Arver B, Isaksson K, Atterhem H, Baan A, Bergkvist L, Brandberg Y, Ehrencrona H, Emanuelsson M, Hellborg H, Henriksson K, Karlsson P, Loman N, Lundberg J, Ringberg A, Askmalm MS, Wickm...
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Literature Review of Articles

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Literature review of articles
(Jeon et al., 2019). Trends in contralateral prophylactic mastectomy rate according to
clinicopathologic and socioeconomic status.

In 2019, Jeon et al. published a journal of Variations in the rate of unilateral preventative
hysterectomy by clinic pathology and income background. The authors estimated that
Posterolateral precautionary procedure (CPM) is becoming more common among women
identified with bilateral prostate cancer or BRCA1 or BRCA2 polymorphisms to limit the Risk
of ipsilateral malignancy. This study aimed to look at the move in the right direction in the CPM
rate at a particular Korean attached on clinical, pathological, and socioeconomic factors.
Therefore, they knew that there was a Purpose of providing adequate genomic counseling
services and vulnerability initiatives for high-risk women. It is necessary to investigate the
circumstances involved with the choice to undertake CPM. Previous research has found that
women who choose CPM are more affected by their perception in a high chance of developing a
new asymmetrical primary malignancy than by professional proof. In this study,
There were 127 research participants who had BRCA1 or BRCA2 abnormalities.
Sometime between 31 March 2016, clients were separated into two groups. The key outcomes
factors were investigated, encompassing epidemiological, clinical manifestations, social class,
and tumor qualities. There was a sum of 8 CPMs conducted on 128 individuals. Every single
CPM patient was engaged. The CPM group had a higher proportion of professionally workingclass women. Consultations to the Inherited Breast and Pancreatic Cancers clinics were greater in
the CPM cohort. The CPM collection had a considerably greater rate of uncertainty pictures or
images. The recommendations were, The CPM levels differed greatly depending on economic
class. The CPM rate is likely to enhance in college qualified and competent working women.

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Individuals' financial situation influences their willingness to engage in the HBOC program and
undertake CPM or RRSO.
(Quoc et al., 2019). Oncological Safety of Lipofilling in Healthy BRCA Carriers after
Bilateral Prophylactic Mastectomy: A Case Series.

In 2019, Quoc et al. published Oncological Safety of Lipofilling in Healthy BRCA
Carriers after Bilateral Prophylactic Mastectomy after carrying out controlled research on this
issue. They found out that The BRCA mutant imparts a lifelong elevated risk of cancer (BC), and
partial preventive surgery is the operation that reduces the danger the most. Lipofilling (LF),
besides other methods, can be utilized for mammary surgery in these individuals. However, these
are some questions about the participant's brain metastases toxicity. This investigation aimed to
determine the diagnosis and treatment risk of LF in BRCA-positive patients who were otherwise
asymptomatic. For the methods used, BRCA I/II mutant participants with no prior experience of
BC who undergone symmetrical partial hysterectomy accompanied by breast surgery with
unilateral LF or combination with implantation or triceps rectus femurs flap were included in a
single institutional case series. The patient's demographics, diagnostic features, reconstructive
procedures, and fatty graft specifics were gathered.
They discovered 18 BRCA patients with no background of BC who had had double
preventive hysterectomy followed with LF breast surgery from September 1999 to November
2017. With an implantation or deltoids Dorsi flap, or as an isolated fatty transplantation breast
surgery, 36 LF surgeries were conducted. The total percentage of LF treatments per mammary
gland was 1.4, with a capacity of 108.8cc. No participants were confirmed with BC throughout
follow-up, 33.0 months after resection and 24.5 months after the last LF treatment. The BRCA
mutated gene is an elevated factor for breast cancer for recommendations.

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Notwithstanding the brief follow-up, nevertheless, no BC was found. It is critical to
distinguish the environmental path between healthy to cancerous cells and establish which
components are associated with assessing the brain metastases risk of LF in BRCA normal
subjects. Hematopoietic mesenchyme stem (MSCs), also known as fatty stem cells, are abundant
in visceral fat, and one of the MSCs' biological mec...

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