The Incidence and Dosimetric Risk Factors of Capsular Contracture in Implant-Based Breast Reconstruction Following Post-Mastectomy Radiotherapy

The Incidence and Dosimetric Risk Factors of Capsular Contracture in Implant-Based Breast Reconstruction Following Post-Mastectomy Radiotherapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Incidence and Dosimetric Risk Factors of Capsular Contracture in Implant-Based Breast Reconstruction Following Post-Mastectomy Radiotherapy Solin Onder, Barbaros Aydin, Ali Ibrahim Sevinc, Hulya Ellidokuz, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8560553/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Objective: In reconstructed breast cancer (RBC) patients, capsular contracture (CC) after radiotherapy (RT) can cause significant cosmetic issues and reduce quality of life. This study aimed to investigate CC incidence and associated risk factors at our center. Methods: Our retrospective study analyzed data from all RBC patients who received RT from June 2014 to January 2025. Chi-square and Fisher’s exact tests were used for categorical variables. Since continuous variables were not normally distributed, the Mann-Whitney U test (MWU) was employed. ROC analysis identified cutoff values for significant variables. Results: A total of 47 implants in 45 patients were analyzed. The median age was 42 (26-57), with a median follow-up of 41 months (5–95). Thirty patients (63.8%) received a permanent prosthesis; 17 (36.2%) had an expander then a prosthesis. Four patients (8.5%) were treated with boost and bolus in 10 (21.3%) cases. Capsular contracture occurred in 8 patients (17%), mainly within 18 months, with 62% being Baker grade 4. No significant relationship was found between CC and categorical variants (all p>0.05). The Dmean of the posterior implant edge (PMI) (p=0.005) and D2% dose (p=0.039) were significantly associated with CC. ROC analysis showed the PMI Dmean had the highest discriminative power (AUROC=0.817), with a cutoff of 5024.5 cGy (75% sensitivity, 94.9% specificity). The PMI D2% dose cutoff was 5265 cGy (62.5% sensitivity, 79.5% specificity). Conclusion: In this study, the PMI Dmean and D2% doses were found to be associated with CC. These findings should be validated in larger studies involving a greater number of patients. Radiotherapy Implant Capsular contracture Dosimetric factors Figures Figure 1 Introduction Breast cancer is the most common cancer type seen in women (1). Due to screening programs, many patients are diagnosed at an early stage, making breast-conserving surgery (BCS) possible (2). However, in some cases (such as multicentric tumors, inflammatory breast cancer, large tumor-to-breast ratio, persistent positive surgical margins after re-excision, and patients with high hereditary risk), mastectomy is inevitable (3, 4, 5, 6). Mastectomy may have adverse effects on cosmetic appearance and psychosocial health (7, 8, 9). After subcutaneous mastectomy with reconstruction (SMR) was confirmed to be non-inferior to conventional mastectomy with superior cosmetic results, it became the most preferred surgical type, especially for young patients (10, 11, 12). However, patients who need post-mastectomy radiotherapy (PMRT) face a higher risk of complications, such as capsular contracture (CC), infection, necrosis, and implant failure (13, 14, 15). Several studies have investigated risk factors associated with CC. These studies identified PMRT, proton therapy, bolus use, and boost as potential risk factors (16, 17, 18). Although some studies highlight the association between dosimetric criteria and construction complications (18), none of the implant-based dosimetric factors were found to be significant in the development of CC (19). In our study, we aimed to investigate the correlation between the dosimetric factors of the implant—categorized into the anterior 1cm area around the implant (AEI), the implant itself, and the posterior margin of the implant (PMI)—and the occurrence of contracture. The objective was to establish dose limits that could minimize adverse cosmetic effects by reducing the risk of CC. Methods Study population and data collection: This study is a retrospective analysis from a single institution which included patients diagnosed with invasive breast cancer who underwent SMR with at least 6 months of follow-up. Patients who underwent breast augmentation before their breast cancer diagnosis were excluded. Systemic Therapy All patients underwent evaluation by a medical oncologist, who selected the most appropriate systemic therapy tailored to each patient's clinical and pathological characteristics and preferences, in alignment with the National Comprehensive Cancer Network (NCCN) guidelines (20). Surgical procedure A team of dedicated oncological and plastic surgeons performed all surgical procedures. Most of the SMRs were completed in one stage with a permanent implant. However, reconstructions involving tissue expanders were carried out in two phases: the SMR was performed simultaneously with the placement of the tissue expander, which was later replaced by a permanent prosthesis in a subsequent surgery. Radiotherapy All patients received PMRT using Varian TrueBeam© (Varian Inc., Palo Alto, CA) version 2.7 linear accelerator systems (LINAC). Patients were positioned supine for simulation, and CT (Siemens Somatom Definition AS) scans were reconstructed with a slice thickness of 3 mm. For eligible patients, a deep inspiration breath-hold (DI-BrTH) technique using the Real‐Time Position Management (RPM) system (Varian Medical Systems, Palo Alto, CA) was utilized. For treatment planning, either the Intensity-Modulated Radiotherapy (IMRT) technique or the Volumetric Arc Therapy (VMAT) was employed, with inverse planning optimization using the Varian Eclipse (version 15.1) treatment planning system (TPS). This planning considered several organs at risk (OAR), including the lungs, heart, left descending artery, brachial plexus, spinal cord, esophagus, and, in cases of right-sided disease, the liver. The target volumes included the chest wall, levels I-III of the axillary lymph nodes, supraclavicular lymph nodes, and internal mammary lymph nodes. Post-mastectomy radiotherapy was administered at a total dose of 50 Gy, delivered in 25 daily fractions of 2 Gy each. For patients presenting with clinical T4 tumors or positive surgical margins, a bolus and boost technique was employed. The boost, targeting the high-risk area, was planned with a dose of 10-16 Gy in 5-8 fractions. This approach aimed to enhance local control in patients with more advanced disease characteristics. Volume Delineation and Dosimetric Factors Both target volume and OAR were delineated according to the RTOG Breast Cancer Atlas (21) and NRG-RTOG 1106 OAR Atlas Thoracic Radiation Therapy (22). To examine the association between dosimetric factors and CC, the implant, the 1 cm area around the anterior edge of the implant (AEI), and the Posterior 5mm margin of the implant (PMI) were retrospectively delineated. Both Dmean and D2% doses of chest wall clinical target volume (CW-CTV), implant, SMI, and PMI were investigated. Supplement-A presents figures that clarify the delineated volumes. Follow-up and capsular contracture assessment During the first two years following PMRT, patients underwent physical examinations every three months. From years three to five, examinations were conducted biannually, and thereafter, they were scheduled annually. Patients undergo monitoring through breast magnetic resonance imaging (MRI) and ultrasound (USG) at least once a year. Capsular contracture was assessed via the clinical Baker scale and verified with MRI changes (23, 24). Statistical analysis Descriptive analyses were utilized to evaluate frequencies within the study population. To assess the relationship between categorical variants and CC, the Chi-square test and Fisher’s Exact tests were conducted. The Shapiro-Wilk test was used to evaluate the normal distribution of numerical variants. Since all numerical variants followed anormal distribution, the Mann-Whitney U (MWU) test was employed. The cut-off values of statistically significant variants were determined through ROC (Receiver Operating Characteristic ) analysis. Univariate and multivariate regression analysis were performed to find independent prognostic factors. Statistical analyses were carried out using the Statistical Package for the Social Sciences (SPSS) version 30. Results A total of 47 prostheses from 45 patients were retrospectively reviewed. The demographic and clinical details of the patients are shown in Table-1. The median age was 42 years (range, 26-57). Disease stages were as follows: Stage I in 5 (10.6%) patients, Stage II in 24 (51.1%) patients, and Stage III in 18 (38.3%) patients. Thirty patients (63.8%) were reconstructed using a permanent prosthesis, whereas seventeen patients (36.2%) underwent reconstruction with an expander followed by a permanent prosthesis after adjuvant radiotherapy. Boost was applied in 4 patients (8.5%). The boost doses varied based on patients' tolerance and the grade of radiodermatitis, with a boost dose of 8Gy in 4 fractions used in 1 patient (2.1%), a dose of 10Gy in 5 fractions applied in 2 patients (4.3%), and a dose of 12Gy in 6 fractions administered in 1 patient (2.1%). All patients had adjuvant radiotherapy with 50Gy in 25 fractions. While IMRT planning was used for 36 (76.6%) of the patients, VMAT was used for 11 (23.4%). Thirty-six patients (76.6%) were treated using the DI-BrTH technique. Bolus was used in 10 patients (21.3%). The median time between surgery and radiotherapy was 2 months (range, 1-40). The median follow-up duration after RT was 41 months (range: 5–95 months). Clinically significant CC, which was defined as Baker grade III-IV, was detected in 8 patients (17%), with 62% being Baker grade 4; all cases occurred within the first 18 months. Only 2 out of 8 patients (25%) with the CC underwent a second surgery. In the Chi-square and Fisher’s exact test, no statistically significant relationship was found between CC and smoking (p=0.69), presence of comorbidities (p=0.094), clinical stage (p=1.000), N stage (p=0.659), histologic sub-type (p=0.613), axillary lymph node dissection (ALND) (p=0.1), grade (p=0.202), molecular sub-type (p=0.993), the time of chemotherapy (p=0.378), HER-2 targeted therapy (p=0.672), implant type (p=0.615), nipple-sparing surgery (p=0.679), the side of the implant (p=0.706), the localisation of the implant (p=0.17), bolus (p=0.55), boost (p=0.129), DI-BrTH (p=0.271) and the technique of RT (p=0.073). Although patients with grade 3 had higher CC rates compared to those with grades 1-2 (30.8% vs. 12.5%, p = 0.202, OR: 2.069, 95% CI: 0.59-7.256), this difference was not statistically significant. Additionally, patients who underwent ALND had a higher CC rate than those without ALND, but this difference did not reach statistical significance (37.5% vs 11.1%, p = 0.10, OR: 4.8, 95% CI: 0.818–28.151). There were higher CC rates in patients who received a boost than in those who did not (p = 0.129, OR: 2.702, 95% CI: 0.817-8.933), although this difference did not reach statistical significance. The technique of RT planning did not reach statistical significance; However, patients treated with VMAT showed a numerically higher incidence of CC than those treated with IMRT (36.4% vs 11.1%, OR: 4.571, 95% CI: 0.914-22.852). According to the MWU test, the mean dose applied to the PMI (p = 0.005) and the D2% dose (p = 0.039) were found to be significantly associated with CC. Meanwhile, age (p = 0.35), the number of dissected lymph nodes (p = 0.987), the volume of the implant (p = 0.427), AEI D2% (p = 0.479), AEI Dmean (p = 0.671), the implant D2% (p = 0.60), the implant Dmean (p = 0.369), the distance between skin and the implant (p = 0.531), and the time between surgery and the start of radiotherapy (p = 0.853) showed no significant association. The results of Fisher's exact tests and MWU tests are shown in Table 2. The ROC analysis, as shown in Figure A, revealed that the mean posterior implant dose parameter exhibited the highest discriminative performance in predicting contracture development (AUROC = 0.817 ± 0.1). The posterior implant D2% dose (AUROC = 0.734 ± 0.1) had moderate discriminative power. Based on this analysis, the optimal cutoff value for PMI Dmean was determined to be 5024.5 cGy, with 75% sensitivity and 94.9% specificity. For the PMI D2% dose, the optimal cutoff was 5265 cGy, with 62.5% sensitivity and 79.5% specificity. In univariate regression analysis, PMI Dmean was associated with the risk of CC after PMRT, with the risk increasing at doses equal to or greater than 5024.5 cGy (p<0.001, OR: 55.5, 95% CI: 6.521-472.372). Additionally, PMI D2% doses of equal or greater than 5265 cGy were associated with an increased risk of CC after PMRT (p=0.025, OR: 6.458, 95% CI: 1.267-32.922). Multivariate regression analysis was performed using variables with p-values < 0.1, which included the presence of comorbidities, ALND, technique of RT, PMI Dmean, and PMI D2%. Only the PMI Dmean was found to be statistically significant, with p= 0.007 (OR: 39.369, 95% CI: 2.749-563.830). Table-1: Displays the clinicopathologic features of patients and tumors. Patient and Tumor Characteristics n (%) T stage T1a, b, c 15 (31.9) T2 23 (48.9) T3 8 (17) T4 1 (2.1) N stage N0 13 (27.7) N1 22 (46.8) N2 11 (23.4) N3 1 (2.1) Clinical stage Stage I 5 (10.7%) Stage II 24 (51.1%) Stage III 18 (38.2%) Histologic subtype IDC* 21 (44.7) ILC** 8 (17) Other type 18 (38.3) Molecular subtype n (%) Luminal-A 16 (34) Luminal-B 15 (31.9) Luminal-B/ HER-2 positive 5 (10.6) HER-2 positive 6 (12.8) TNBC*** 5 (10.6) ALND ˚ Yes 8 (17) No 36 (76.6%) Unknown 3 (6.4%) Reconstruction type Permanent prosthesis 30 (63.8) Expander 17 (36.2) Localisation Supra-pectoral 1 (2.1) Sub-pectoral 46 (97.9) Nipple sparing surgery Yes 33 (70.2) No 14 (29.8) Chemotherapy Neoadjuvant 33 (70.2) Adjuvant 11 (23.4) DI-BrTH ͤ Yes 36 (76.6) No 11 (23.4) Boost Yes 4 (8.5) No 43 (91.5) Bolus Yes 10 (21.3) No 37 (78.7) RT technique IMRT 36 (76.6) VMAT 11 (23.4) Median (range) Age, 42 (26-57) DLN ˚˚ 4 (1-30) Volume˜ 325 (100-590) *IDC: Invasive ductal carcinoma **ILC: Invasive lobular carcinoma ***TNBC: triple negative breast cancer ˚ALND: Axillary lymph node dissection ˚˚DLN: Number of dissected lymph nodes ͂ Volume of the implant ͤ DI-BrTH: Deep inspiration breath-hold Table-2: The results of the Fisher's exact test and the MWU tests Variable P Value OR (95%CI)* Age 0.35 1.052 (0.944-1.173) Smoking 0.69 1.283 (0.475-3.47) Presence of comorbidities 0.094 1.812 (0.902-3.642) Clinical stage 1.00 1.083 (0.592-1.983) T stage 1.00 1.257 (0.695-2.275) N stage 0.659 0.776 (0.37-1.627) Histologic sub-type 0.613 0.782 (0.329-1.857) Grade 0.202 2.069 (0.59-7.256) Molecular sub-type 0.993 1.023 (0.583-1.797) Time of chemotherapy 0.378 1.426 (0.332-6.134) HER-2 targeted therapy 0.672 0.967 (0.167-5.587) ALND 0.1 4.8 (0.818 – 28.151) DLN** 0.987 1.058 (0.962-1.164) Implant type 0.615 1.071 (0.222-5.17) Nipple-sparing surgery 0.679 0.655 (0.133-3.218) Side of the implant 0.706 0.632 (0.132-3.015) Localisation of the implant 0.17 NE ʃ Volume of the implant 0.427 1.005 (0.997-1.012) Time*** 0.853 1.001 (0.876-1.142) PTV D2% 0.562 1.002 (1.000-1.004) PTV Dmean 0.293 1.002 (1.000-1.005) CTV D2% 0.569 1.002 (1.000-1.004) CTV Dmean 0.153 1.005 (1.000-1.010) AEI D2% 0.479 1.002 (1.000-1.004) AEI Dmean 0.671 1.001 (0.999-1.003) AEI D2% ¹ 0.256 1.002 (1.000-1.005) AEI Dmean ¹ 0.616 1.002 (1.000-1.005) AEI D2% ² 0.526 1.003 (1.000-1.005) AEI Dmean ² 0.593 1.003 (1.000-1.005) Implant D2% 0.6 1.002 (1.000-1.004) Implant Dmean 0.369 1.004 (1.000-1.008) Implant D2% ¹ 0.256 1.003 (1.000-1.005) Implant Dmean ¹ 0.120 1.004 (1.000-1.008) Implant D2% ² 0.367 1.003 (1.000-1.005) Implant Dmean ² 0.171 1.005 (1.000-1.009) PMI Dmean 0.005 55.5 (6.521-472.372) PMI D2% 0.039 6.458 (1.267-32.922) Distance˚ 0.531 1.077 (0.948-1.225) Bolus 0.55 1.292 (0.218-7.652) Boost 0.129 2.702 (0.817-8.933) DI-BrTH 0.271 0.43 (0.0844-2.193) Technique of RT 0.073 4.571 (0.914-22.852) *according to univariate regression analysis **DLN: Number of dissected lymph nodes ʃ Due to the limited number of each group ***Time between surgery and the start of radiotherapy ˚The distance between the skin and the implant ¹The part of the implant situated between the pectoral muscles ²The part of the implant situated outside the pectoral minor muscles Discussion Our trial used retrospective data from a single center to analyze the incidence of clinically significant CC in patients who underwent SMR and PMRT. We also investigated potential clinical and dosimetric risk factors related to this issue, which can cause numerous economic and psychosocial effects. In our patients, clinically significant CC was observed in 8 (17%) individuals, resulting in implant loss in 25% of these affected patients. This aligns with other data in the literature, which report the CC range to be between 7% and 32% (13, 16, 25). We were unable to identify any prognostic clinical factors associated with the risk of CC. However, there were numerically more CC rates in patients with grade 3 than in those with grades 1 and 2. One of the hypotheses that explains these results is that inflammatory markers have been documented as being associated with the formation and severity of capsular contracture, suggesting that the biological behavior of higher-grade tumors may contribute to a more pronounced inflammatory response around implant materials (26, 27, 28). Additionally, we found that the CC rates were numerically higher in patients who underwent ALND, although this difference did not achieve statistical significance. However, some trials have confirmed the prognostic value of extensive nodal surgery in reducing the risk of CC (29). We believe that the lack of statistical significance in our trial was due to the limited study size. There were higher CC rates in patients who had a boost, but this difference was not statistically significant due to the small study size. However, some trials confirm the prognostic value of boost for Capsular-related complications (30). Our study is the first to investigate dosimetric factors of the implant by dividing it into regions: the area in front of the implant, the implant itself, and the posterior area. Additionally, we categorize regions based on their location between the pectoralis minor and major muscles and outside the pectoralis minor. Our analysis revealed that the Dmean and D2% of the PMI were both statistically significant indicators, capable of predicting the risk of CC with good and moderate discriminatory power, respectively (AUROC = 0.817 ± 0.1 and 0.734 ± 0.1, respectively). Based on our current knowledge, we cannot definitively state the exact reason for the association between PMI doses and the risk of CC. However, we believe that PMI has increased blood supply, which may promote inflammation in that area and contribute to CC. Additionally, higher doses of PMI are linked to an increased risk of muscle fibrosis, which could also contribute to CC (31, 32). Our study has several limitations, including a small sample size, a retrospective design, single-center data, and limited follow-up time. Nevertheless, it is the first in the literature to analyze the dosimetric factors of the anterior area of the implant, the implant itself, and the posterior margin. It is also the first to investigate dosimetric factors by categorizing implants into parts situated between the pectoralis minor and major muscles, and parts outside the pectoralis minor. Furthermore, it is the first to demonstrate the prognostic significance of posterior margin doses for the risk of CC. These unique aspects contribute valuable knowledge to both academic literature and clinical practice. Conclusion Our trial highlighted the significance of PMI doses for CC. According to our findings, PMI Dmean dose of 5024.5 cGy and D2% dose of 5265 cGy can serve as dose constraints to prevent capsular contracture. Additional validation with larger sample sizes and prospective studies is necessary to confirm these findings. Abbreviations RBC: reconstructed breast cancer CC: capsular contracture RT: radiotherapy ROC: Receiver Operating Characteristic BCS: breast-conserving surgery SMR: subcutaneous mastectomy with reconstruction PMRT: post-mastectomy radiotherapy AEI: the anterior 1cm area around the implant PMI: the posterior margin of the implant NCCN: National Comprehensive Cancer Network LINAC: linear accelerator IMRT: Intensity-Modulated Radiotherapy VMAT: Volumetric Arc Therapy TPS: treatment planning system OAR: organs at risk CTV: clinical target volume USG: ultrasound MRI: magnetic resonance imaging MWU: Mann-Whitney U SPSS: the Statistical Package for the Social Sciences ALND: axillary lymph node dissection Declarations Ethics approval and consent to participate: Our trial received approval from the Dokuz Eylul University Ethics Committee and was conducted in accordance with the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all participants. Consent for publication: A consent for publication was obtained from participants Consent for the publication of identifying images or other personal or clinical details of participants that compromise anonymity: Not Applicable Availability of Data and Materials: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing interests: The authors declare that they have no competing interests Funding: Not applicable Authors' contributions: SO prepared the datasets of the patients who participated in the trial, retrospectively delineated the patients’ volumes, contributed to the patients’ clinical assessment, and wrote the article, and was a major contributor to the manuscript. BA contributed to patient selection, contour evaluation, contracture assessment, patients' clinical examination, scoring the degree of contracture, article writing, and review. AIS was responsible for the surgery and the patient's clinical examination and follow-up. HE was responsible for statistical analysis IBA was responsible for evaluating the radiological images and scoring of capsular contracture IG was responsible for the article review and patient's examination All authors read and approved the final manuscript. Acknowledgements: Not applicable Authors' information (optional) References Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023 Jan;73(1):17-48. doi: 10.3322/caac.21763. PMID: 36633525. Bleyer, A., & Welch, H. (2012). Effect of three decades of screening mammography on breast-cancer incidence. The New England journal of medicine , 367 21, 1998-2005 . https://doi.org/10.1056/nejmoa1206809. Matthijs V. Nijenhuis, Emiel J.Th. Rutgers, Emiel JTh Rutgers, Matthijs V Nijenhuis, Emiel J Th Rutgers, M. V. Nijenhuis, Emiel J. T. Rutgers. (2015). Conservative surgery for multifocal/multicentric breast cancer. 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Kong, F., Ritter, T., Quint, D., Senan, S., Gaspar, L., Komaki, R., Hurkmans, C., Timmerman, R., Bezjak, A., Bradley, J., Movsas, B., Marsh, L., Okunieff, P., Choy, H., & Curran, W. (2011). Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus. International journal of radiation oncology, biology, physics , 81 5, 1442-57. https://doi.org/10.1016/j.ijrobp.2010.07.1977. De Bakker, E., Rots, M., Buncamper, M., Niessen, F., Smit, J., Winters, H., Özer, M., De Vet, H., & Mullender, M. (2020). The Baker Classification for Capsular Contracture in Breast Implant Surgery Is Unreliable as a Diagnostic Tool. Plastic and Reconstructive Surgery , 146, 956 - 962. https://doi.org/10.1097/prs.0000000000007238. Tyagi, N., Sutton, E., Hunt, M., Zhang, J., Oh, J., Apte, A., Mechalakos, J., Wilgucki, M., Gelb, E., Mehrara, B., Matros, E., & Ho, A. (2016). Morphologic Features of Magnetic Resonance Imaging as a Surrogate of Capsular Contracture in Breast Cancer Patients With Implant-based Reconstructions. International journal of radiation oncology, biology, physics , 97 2, 411-419. https://doi.org/10.1016/j.ijrobp.2016.09.041. Cowen, D., Gross, E., Rouannet, P., Teissier, E., Ellis, S., Resbeut, M., T., Cowen, V., Azria, D., & Hannoun-Levi, J. (2010). Immediate post-mastectomy breast reconstruction followed by radiotherapy: risk factors for complications. Breast Cancer Research and Treatment , 121, 627-634. https://doi.org/10.1007/s10549-010-0791-5. Safran T, Nepon H, Chu CK, Winocour S, Murphy AM, Davison PG, Dionisopolos T, Vorstenbosch J. Current Concepts in Capsular Contracture: Pathophysiology, Prevention, and Management. Semin Plast Surg. 2021 Aug;35(3):189-197. doi: 10.1055/s-0041-1731793. Epub 2021 Jul 13. PMID: 34526867; PMCID: PMC8432999. Liu, S., Lachapelle, J., Leung, S. et al. CD8 + lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res 14 , R48 (2012). https://doi.org/10.1186/bcr3148 Sahar M.A. Mahmoud et al. Tumor-Infiltrating CD8 + Lymphocytes Predict Clinical Outcome in Breast Cancer. J Clin Oncol 29 , 1949-1955(2011), DOI:10.1200/JCO.2010.30.5037 Lee, J., Lee, H., Jeon, S., Kim, D., Lee, Y., Bae, S., Park, W., Yoon, C., & Choi, J. (2025). Impact of Chemotherapy on Implant-Based Breast Reconstruction in Breast Cancer Patients: A Nationwide, Retrospective, Cohort Study. Cancers, 17. https://doi.org/10.3390/cancers17122053 Naoum GE, Salama L, Ho A, Horick NK, Oladeru O, Abouegylah M, Daniell K, MacDonald S, Arafat WO, Smith BL, Colwell AS, Taghian AG. The Impact of Chest Wall Boost on Reconstruction Complications and Local Control in Patients Treated for Breast Cancer. Int J Radiat Oncol Biol Phys. 2019 Sep 1;105(1):155-164. doi: 10.1016/j.ijrobp.2019.04.027. Epub 2019 May 2. PMID: 31055108. Sobti, N., Weitzman, R., Nealon, K., Jimenez, R., Gfrerer, L., Mattos, D., Ehrlichman, R., Gadd, M., Specht, M., Austen, W., & Liao, E. (2020). Evaluation of capsular contracture following immediate prepectoral versus subpectoral direct-to-implant breast reconstruction. Scientific Reports , 10. https://doi.org/10.1038/s41598-020-58094-4. Kobraei EM, Cauley R, Gadd M, Austen WG Jr, Liao EC. Avoiding Breast Animation Deformity with Pectoralis-Sparing Subcutaneous Direct-to-Implant Breast Reconstruction. Plast Reconstr Surg Glob Open. 2016 May 27;4(5):e708. doi: 10.1097/GOX.0000000000000681. PMID: 27579232; PMCID: PMC4995704. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8560553","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":587609587,"identity":"bdf41f2e-1f4a-4dbd-a902-4d9a53347716","order_by":0,"name":"Solin Onder","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYFAC5oYDYPoAA+MDHjArgZAWRrgWZgO4lgMEtDBAtbBJEKVFvr2x8XABg00e3/HeZxVvKg4z8LPnGDB/3INbi8GZgw2HZzCkFUueOW52c86ZwwySPW8MGA48w6NFIrHhMA/D4cQNN9LYbvO2HWYwuJED1ILHZfIzYFruP2Mr5v13mMGekBaGG3Bb2NiYeRuAtkgQ0AL2C49BWuLMM2nMknOOpfNInHlWcOAMPoe1Nx/+zFNhk9h3/Bjjhzc11nL87ckbH1TgcxjELgQTHDUENYyCUTAKRsEowA8Ab2VZbgVvZoYAAAAASUVORK5CYII=","orcid":"","institution":"Dokuz Eylül University","correspondingAuthor":true,"prefix":"","firstName":"Solin","middleName":"","lastName":"Onder","suffix":""},{"id":587609588,"identity":"dbb6d9cc-91e4-415e-92f8-c021a20f0308","order_by":1,"name":"Barbaros Aydin","email":"","orcid":"","institution":"Dokuz Eylül University","correspondingAuthor":false,"prefix":"","firstName":"Barbaros","middleName":"","lastName":"Aydin","suffix":""},{"id":587609590,"identity":"ac4b623e-4a74-469f-ae68-b1cfd0f35b17","order_by":2,"name":"Ali Ibrahim Sevinc","email":"","orcid":"","institution":"Dokuz Eylül University","correspondingAuthor":false,"prefix":"","firstName":"Ali","middleName":"Ibrahim","lastName":"Sevinc","suffix":""},{"id":587609593,"identity":"414c0d4c-0a38-4d03-991a-51de6d246d07","order_by":3,"name":"Hulya Ellidokuz","email":"","orcid":"","institution":"Dokuz Eylül University","correspondingAuthor":false,"prefix":"","firstName":"Hulya","middleName":"","lastName":"Ellidokuz","suffix":""},{"id":587609595,"identity":"e56ddd3f-910f-4891-8d9c-8801baf4c4bd","order_by":4,"name":"Isil Basara Akin","email":"","orcid":"","institution":"Dokuz Eylül University","correspondingAuthor":false,"prefix":"","firstName":"Isil","middleName":"Basara","lastName":"Akin","suffix":""},{"id":587609596,"identity":"7e60cd42-6d46-45dc-b1d1-a0dfdce87975","order_by":5,"name":"Ilknur Gorken","email":"","orcid":"","institution":"Dokuz Eylül University","correspondingAuthor":false,"prefix":"","firstName":"Ilknur","middleName":"","lastName":"Gorken","suffix":""}],"badges":[],"createdAt":"2026-01-09 11:38:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8560553/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8560553/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102326336,"identity":"2b376ddc-0096-4946-9f4b-82ea4fa48ade","added_by":"auto","created_at":"2026-02-10 14:35:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":56929,"visible":true,"origin":"","legend":"\u003cp\u003eillustrates the ROC analysis results, highlighting the impact of PMI Dmean and D2% on CC prevalence.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8560553/v1/3ade2a5bda9dd98ed424dde7.png"},{"id":102397726,"identity":"886cd7fa-e558-4358-94b2-109cf7aaacea","added_by":"auto","created_at":"2026-02-11 10:19:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":891231,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8560553/v1/faa5f2da-8740-4efe-ad34-0bb2abb19e7c.pdf"},{"id":102326337,"identity":"f15f1714-2833-433d-81b7-45d3c977bb8a","added_by":"auto","created_at":"2026-02-10 14:35:06","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":1017387,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementA.docx","url":"https://assets-eu.researchsquare.com/files/rs-8560553/v1/911cabd13416e3298b8e99c4.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Incidence and Dosimetric Risk Factors of Capsular Contracture in Implant-Based Breast Reconstruction Following Post-Mastectomy Radiotherapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer is the most common cancer type seen in women (1). Due to screening programs, many patients are diagnosed at an early stage, making breast-conserving surgery (BCS) possible (2). However, in some cases (such as multicentric tumors, inflammatory breast cancer, large tumor-to-breast ratio, persistent positive surgical margins after re-excision, and patients with high hereditary risk), mastectomy is inevitable (3, 4, 5, 6).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMastectomy may have adverse effects on cosmetic appearance and psychosocial health (7, 8, 9). After subcutaneous mastectomy with reconstruction (SMR) was confirmed to be non-inferior to conventional mastectomy with superior cosmetic results, it became the most preferred surgical type, especially for young patients (10, 11, 12).\u003c/p\u003e\n\u003cp\u003eHowever, patients who need post-mastectomy radiotherapy (PMRT) face a higher risk of complications, such as capsular contracture (CC), infection, necrosis, and implant failure (13, 14, 15).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSeveral studies have investigated risk factors associated with CC. These studies identified PMRT, proton therapy, bolus use, and boost as potential risk factors (16, 17, 18). Although some studies highlight the association between dosimetric criteria and construction complications (18), none of the implant-based dosimetric factors were found to be significant in the development of CC (19).\u003c/p\u003e\n\u003cp\u003eIn our study, we aimed to investigate the correlation between the dosimetric factors of the implant\u0026mdash;categorized into the anterior 1cm area around the implant (AEI), the implant itself, and the posterior margin of the implant (PMI)\u0026mdash;and the occurrence of contracture. The objective was to establish dose limits that could minimize adverse cosmetic effects by reducing the risk of CC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy population and data collection:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a retrospective analysis from a single institution which included patients diagnosed with invasive breast cancer who underwent SMR with at least 6 months of follow-up. Patients who underwent breast augmentation before their breast cancer diagnosis were excluded.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSystemic Therapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients underwent evaluation by a medical oncologist, who selected the most appropriate systemic therapy tailored to each patient\u0026apos;s clinical and pathological characteristics and preferences, in alignment with the National Comprehensive Cancer Network (NCCN) guidelines (20).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurgical procedure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA team of dedicated oncological and plastic surgeons performed all surgical procedures. Most of the SMRs were completed in one stage with a permanent implant. However, reconstructions involving tissue expanders were carried out in two phases: the SMR was performed simultaneously with the placement of the tissue expander, which was later replaced by a permanent prosthesis in a subsequent surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRadiotherapy\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients received PMRT using Varian TrueBeam\u0026copy; (Varian Inc., Palo Alto, CA) version 2.7 linear accelerator systems (LINAC). Patients were positioned supine for simulation, and CT (Siemens Somatom Definition AS) scans were reconstructed with a slice thickness of 3 mm. For eligible patients, a deep inspiration breath-hold (DI-BrTH) technique using the Real‐Time Position Management (RPM) system (Varian Medical Systems, Palo Alto, CA) was utilized. For treatment planning, either the Intensity-Modulated Radiotherapy (IMRT) technique or the Volumetric Arc Therapy (VMAT) was employed, with inverse planning optimization using the Varian Eclipse (version 15.1) treatment planning system (TPS). This planning considered several organs at risk (OAR), including the lungs, heart, left descending artery, brachial plexus, spinal cord, esophagus, and, in cases of right-sided disease, the liver. The target volumes included the chest wall, levels I-III of the axillary lymph nodes, supraclavicular lymph nodes, and internal mammary lymph nodes. Post-mastectomy radiotherapy was administered at a total dose of 50 Gy, delivered in 25 daily fractions of 2 Gy each. For patients presenting with clinical T4 tumors or positive surgical margins, a bolus and boost technique was employed. The boost, targeting the high-risk area, was planned with a dose of 10-16 Gy in 5-8 fractions. This approach aimed to enhance local control in patients with more advanced disease characteristics.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVolume Delineation and Dosimetric Factors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBoth target volume and OAR were delineated according to the RTOG Breast Cancer Atlas (21) and NRG-RTOG 1106 OAR Atlas Thoracic Radiation Therapy (22). To examine the association between dosimetric factors and CC, the implant, the 1 cm area around the anterior edge of the implant (AEI), and the Posterior 5mm margin of the implant (PMI) were retrospectively delineated. Both Dmean and D2% doses of chest wall clinical target volume (CW-CTV), implant, SMI, and PMI were investigated. Supplement-A presents figures that clarify the delineated volumes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up and capsular contracture assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the first two years following PMRT, patients underwent physical examinations every three months. From years three to five, examinations were conducted biannually, and thereafter, they were scheduled annually. Patients undergo monitoring through breast magnetic resonance imaging (MRI) and ultrasound (USG) at least once a year. Capsular contracture was assessed via the clinical Baker scale and verified with MRI changes (23, 24).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDescriptive analyses were utilized to evaluate frequencies within the study population. To assess the relationship between categorical variants and CC, the Chi-square test and Fisher\u0026rsquo;s Exact tests were conducted. \u0026nbsp;The Shapiro-Wilk test was used to evaluate the normal distribution of numerical variants. Since all numerical variants followed anormal distribution, the Mann-Whitney U (MWU) test was employed. The cut-off values of statistically significant variants were determined through ROC (Receiver\u0026nbsp;Operating Characteristic\u003cstrong\u003e)\u0026nbsp;\u003c/strong\u003eanalysis. Univariate and multivariate regression analysis were performed to find independent prognostic factors. Statistical analyses were carried out using the Statistical Package for the Social Sciences (SPSS) version 30.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 47 prostheses from 45 patients were retrospectively reviewed. The demographic and clinical details of the patients are shown in Table-1. The median age was 42 years (range, 26-57). Disease stages were as follows: Stage I in 5 (10.6%) patients, Stage II in 24 (51.1%) patients, and Stage III in 18 (38.3%) patients. \u0026nbsp;Thirty patients (63.8%) were reconstructed using a permanent prosthesis, whereas seventeen patients (36.2%) underwent reconstruction with an expander followed by a permanent prosthesis after adjuvant radiotherapy. Boost was applied in 4 patients (8.5%). The boost doses varied based on patients\u0026apos; tolerance and the grade of radiodermatitis, with a boost dose of 8Gy in 4 fractions used in 1 patient (2.1%), a dose of 10Gy in 5 fractions applied in 2 patients (4.3%), and a dose of 12Gy in 6 fractions administered in 1 patient (2.1%). All patients had adjuvant radiotherapy with 50Gy in 25 fractions. While IMRT planning was used for 36 (76.6%) of the patients, VMAT was used for 11 (23.4%). Thirty-six patients (76.6%) were treated using the DI-BrTH technique. Bolus was used in 10 patients (21.3%). \u0026nbsp;The median time between surgery and radiotherapy was 2 months (range, 1-40). The median follow-up duration after RT was 41 months (range: 5\u0026ndash;95 months).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eClinically significant CC, which was defined as Baker grade III-IV, was detected in 8 patients (17%), with 62% being Baker grade 4; all cases occurred within the first 18 months. Only 2 out of 8 patients (25%) with the CC underwent a second surgery.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the Chi-square and Fisher\u0026rsquo;s exact test, no statistically significant relationship was found between CC and smoking (p=0.69), presence of comorbidities (p=0.094), clinical stage (p=1.000), N stage (p=0.659), histologic sub-type (p=0.613), axillary lymph node dissection (ALND) (p=0.1), grade (p=0.202), molecular sub-type (p=0.993), \u0026nbsp;the time of chemotherapy (p=0.378), HER-2 targeted therapy (p=0.672), implant type (p=0.615), nipple-sparing surgery (p=0.679), the side of the implant (p=0.706), the localisation of the implant (p=0.17), bolus (p=0.55), boost (p=0.129), DI-BrTH \u0026nbsp;(p=0.271) and the technique of RT (p=0.073). Although patients with grade 3 had higher CC rates compared to those with grades 1-2 (30.8% vs. 12.5%, p = 0.202, OR: 2.069, 95% CI: 0.59-7.256), this difference was not statistically significant. Additionally, patients who underwent ALND had a higher CC rate than those without ALND, but this difference did not reach statistical significance (37.5% vs 11.1%, p = 0.10, OR: 4.8, 95% CI: 0.818\u0026ndash;28.151). There were higher CC rates in patients who received a boost than in those who did not (p = 0.129, OR: 2.702, 95% CI: 0.817-8.933), although this difference did not reach statistical significance. The technique of RT planning did not reach statistical significance; However, patients treated with VMAT showed a numerically higher incidence of CC than those treated with IMRT (36.4% vs 11.1%, OR: 4.571, 95% CI: 0.914-22.852).\u003c/p\u003e\n\u003cp\u003eAccording to the MWU test, the mean dose applied to the PMI (p = 0.005) and the D2% dose (p = 0.039) were found to be significantly associated with CC. Meanwhile, age (p = 0.35), the number of dissected lymph nodes (p = 0.987), the volume of the implant (p = 0.427), AEI D2% (p = 0.479), AEI Dmean (p = 0.671), the implant D2% (p = 0.60), the implant Dmean (p = 0.369), the distance between skin and the implant (p = 0.531), and the time between surgery and the start of radiotherapy (p = 0.853) showed no significant association. The results of Fisher\u0026apos;s exact tests and MWU tests are shown in Table 2.\u003c/p\u003e\n\u003cp\u003eThe ROC analysis, as shown in Figure A, revealed that the mean posterior implant dose parameter exhibited the highest discriminative performance in predicting contracture development (AUROC = 0.817 \u0026plusmn; 0.1). The posterior implant D2% dose (AUROC = 0.734 \u0026plusmn; 0.1) had moderate discriminative power. Based on this analysis, the optimal cutoff value for PMI Dmean was determined to be 5024.5 cGy, with 75% sensitivity and 94.9% specificity. For the PMI D2% dose, the optimal cutoff was 5265 cGy, with 62.5% sensitivity and 79.5% specificity.\u003c/p\u003e\n\u003cp\u003eIn univariate regression analysis, PMI Dmean was associated with the risk of CC after PMRT, with the risk increasing at doses equal to or greater than 5024.5 cGy (p\u0026lt;0.001, OR: 55.5, 95% CI: 6.521-472.372). Additionally, PMI D2% doses of equal or greater than 5265 cGy were associated with an increased risk of CC after PMRT (p=0.025, OR: 6.458, 95% CI: 1.267-32.922).\u003c/p\u003e\n\u003cp\u003eMultivariate regression analysis was performed using variables with p-values \u003cu\u003e\u0026lt;\u003c/u\u003e0.1, which included the presence of comorbidities, ALND, technique of RT, PMI Dmean, and PMI D2%. Only the PMI Dmean was found to be statistically significant, with p= 0.007 (OR: 39.369, 95% CI: 2.749-563.830).\u003c/p\u003e\n\u003cp\u003eTable-1: Displays the clinicopathologic features of patients and tumors.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient and Tumor Characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; T1a, b, c\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e15 (31.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; T2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e23 (48.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;T3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e8 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; T4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; N0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e13 (27.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;N1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e22 (46.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; N2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e11 (23.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;N3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Stage I\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e5 (10.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; Stage II\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e24 (51.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Stage III\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e18 (38.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistologic subtype\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;IDC*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e21 (44.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; ILC**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e8 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Other type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e18 (38.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMolecular subtype\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Luminal-A\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e16 (34)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp;Luminal-B\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e15 (31.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Luminal-B/ HER-2 positive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e5 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp;HER-2 positive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e6 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; TNBC***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e5 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eALND\u003c/strong\u003e\u003cstrong\u003e˚\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Yes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e8 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e36 (76.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Unknown\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e3 (6.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReconstruction type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Permanent prosthesis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e30 (63.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Expander\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e17 (36.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocalisation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Supra-pectoral\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Sub-pectoral\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e46 (97.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNipple sparing surgery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Yes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e33 (70.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e14 (29.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Neoadjuvant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e33 (70.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Adjuvant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e11 (23.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDI-BrTH\u003c/strong\u003e\u003cstrong\u003eͤ\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Yes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e36 (76.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e11 (23.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBoost\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Yes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e43 (91.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBolus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Yes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e10 (21.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;No\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e37 (78.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRT technique\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; IMRT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e36 (76.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; VMAT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e11 (23.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge,\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e42 (26-57)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDLN\u003c/strong\u003e\u003cstrong\u003e˚˚\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4 (1-30)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVolume\u0026tilde;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e325 (100-590)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;*IDC: Invasive ductal carcinoma\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e**ILC: Invasive lobular carcinoma\u003c/p\u003e\n\u003cp\u003e***TNBC: triple negative breast cancer\u003c/p\u003e\n\u003cp\u003e˚ALND: Axillary lymph node dissection\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e˚˚DLN: Number of dissected lymph nodes\u003c/p\u003e\n\u003cp\u003e͂\u0026nbsp;Volume of the implant\u003c/p\u003e\n\u003cp\u003eͤ DI-BrTH: Deep inspiration breath-hold \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable-2: The results of the Fisher\u0026apos;s exact test and the MWU tests\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eP Value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eOR (95%CI)*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.052 (0.944-1.173)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.283 (0.475-3.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003ePresence of comorbidities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.094\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.812 (0.902-3.642)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eClinical stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.083 (0.592-1.983)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eT stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.257 (0.695-2.275)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eN stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.659\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e0.776 (0.37-1.627)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eHistologic sub-type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.613\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e0.782 (0.329-1.857)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eGrade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.202\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e2.069 (0.59-7.256)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eMolecular sub-type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.993\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.023 (0.583-1.797)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eTime of chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.378\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.426 (0.332-6.134)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eHER-2 targeted therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.672\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e0.967 (0.167-5.587)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eALND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e4.8 (0.818 \u0026ndash; 28.151)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eDLN**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.987\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.058 (0.962-1.164)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eImplant type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.615\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.071 (0.222-5.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eNipple-sparing surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.679\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e0.655 (0.133-3.218)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eSide of the implant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.706\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e0.632 (0.132-3.015)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eLocalisation of the implant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eNE ʃ\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eVolume of the implant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.427\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.005 (0.997-1.012)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eTime***\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.853\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.001 (0.876-1.142)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003ePTV D2%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.562\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.002 (1.000-1.004)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003ePTV Dmean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.293\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.002 (1.000-1.005)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eCTV D2%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.569\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.002 (1.000-1.004)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eCTV Dmean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.005 (1.000-1.010)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eAEI D2%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.479\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.002 (1.000-1.004)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eAEI Dmean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.671\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.001 (0.999-1.003)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eAEI D2%\u0026nbsp;\u0026sup1;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.256\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.002 (1.000-1.005)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eAEI Dmean\u0026nbsp;\u0026sup1;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.616\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.002 (1.000-1.005)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eAEI D2%\u0026nbsp;\u0026sup2;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.526\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.003 (1.000-1.005)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eAEI Dmean\u0026nbsp;\u0026sup2;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.593\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.003 (1.000-1.005)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eImplant D2%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.002 (1.000-1.004)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eImplant Dmean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.369\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.004 (1.000-1.008)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eImplant D2%\u0026nbsp;\u0026sup1;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.256\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.003 (1.000-1.005)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eImplant Dmean\u0026nbsp;\u0026sup1;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.004 (1.000-1.008)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eImplant D2%\u0026nbsp;\u0026sup2;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.367\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.003 (1.000-1.005)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eImplant Dmean\u0026nbsp;\u0026sup2;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.005 (1.000-1.009)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePMI Dmean\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e55.5 (6.521-472.372)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePMI D2%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.039\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6.458 (1.267-32.922)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eDistance˚\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.531\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.077 (0.948-1.225)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eBolus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e1.292 (0.218-7.652)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eBoost\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e2.702 (0.817-8.933)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eDI-BrTH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.271\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e0.43 (0.0844-2.193)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eTechnique of RT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e0.073\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e4.571 (0.914-22.852)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e*according to univariate regression analysis\u003c/p\u003e\n\u003cp\u003e**DLN: Number of dissected lymph nodes\u003c/p\u003e\n\u003cp\u003eʃ Due to the limited number of each group\u003c/p\u003e\n\u003cp\u003e***Time between surgery and the start of radiotherapy\u003c/p\u003e\n\u003cp\u003e˚The distance between the skin and the implant\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026sup1;The part of the implant situated between the pectoral muscles\u003c/p\u003e\n\u003cp\u003e\u0026sup2;The part of the implant situated outside the pectoral minor muscles\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur trial used retrospective data from a single center to analyze the incidence of clinically significant CC in patients who underwent SMR and PMRT. We also investigated potential clinical and dosimetric risk factors related to this issue, which can cause numerous economic and psychosocial effects.\u003c/p\u003e\n\u003cp\u003eIn our patients, clinically significant CC was observed in 8 (17%) individuals, resulting in implant loss in 25% of these affected patients. This aligns with other data in the literature, which report the CC range to be between 7% and 32% (13, 16, 25).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe were unable to identify any prognostic clinical factors associated with the risk of CC. However, there were numerically more CC rates in patients with grade 3 than in those with grades 1 and 2. One of the hypotheses that explains these results is that inflammatory markers have been documented as being associated with the formation and severity of capsular contracture, suggesting that the biological behavior of higher-grade tumors may contribute to a more pronounced inflammatory response around implant materials (26, 27, 28).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdditionally, we found that the CC rates were numerically higher in patients who underwent ALND, although this difference did not achieve statistical significance. However, some trials have confirmed the prognostic value of extensive nodal surgery in reducing the risk of CC (29). We believe that the lack of statistical significance in our trial was due to the limited study size.\u003c/p\u003e\n\u003cp\u003eThere were higher CC rates in patients who had a boost, but this difference was not statistically significant due to the small study size. \u0026nbsp; However, some trials confirm the prognostic value of boost for Capsular-related complications (30).\u003c/p\u003e\n\u003cp\u003eOur study is the first to investigate dosimetric factors of the implant by dividing it into regions: the area in front of the implant, the implant itself, and the posterior area. Additionally, we categorize regions based on their location between the pectoralis minor and major muscles and outside the pectoralis minor.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur analysis revealed that the Dmean and D2% of the PMI were both statistically significant indicators, capable of predicting the risk of CC with good and moderate discriminatory power, respectively (AUROC = 0.817 \u0026plusmn; 0.1 and 0.734 \u0026plusmn; 0.1, respectively).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBased on our current knowledge, we cannot definitively state the exact reason for the association between PMI doses and the risk of CC. However, we believe that PMI has increased blood supply, which may promote inflammation in that area and contribute to CC. Additionally, higher doses of PMI are linked to an increased risk of muscle fibrosis, which could also contribute to CC (31, 32).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study has several limitations, including a small sample size, a retrospective design, single-center data, and limited follow-up time. Nevertheless, it is the first in the literature to analyze the dosimetric factors of the anterior area of the implant, the implant itself, and the posterior margin. It is also the first to investigate dosimetric factors by categorizing implants into parts situated between the pectoralis minor and major muscles, and parts outside the pectoralis minor. Furthermore, it is the first to demonstrate the prognostic significance of posterior margin doses for the risk of CC. These unique aspects contribute valuable knowledge to both academic literature and clinical practice.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur trial highlighted the significance of PMI doses for CC. According to our findings, PMI Dmean dose of 5024.5 cGy and D2% dose of 5265 cGy can serve as dose constraints to prevent capsular contracture. Additional validation with larger sample sizes and prospective studies is necessary to confirm these findings.\u0026nbsp;\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eRBC: reconstructed breast cancer\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCC: capsular contracture\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRT: radiotherapy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eROC: Receiver Operating Characteristic\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBCS: breast-conserving surgery\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSMR: subcutaneous mastectomy with reconstruction\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePMRT: post-mastectomy radiotherapy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAEI: the anterior 1cm area around the implant\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePMI: the posterior margin of the implant\u003c/p\u003e\n\u003cp\u003eNCCN: National Comprehensive Cancer Network \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLINAC: linear accelerator\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIMRT: Intensity-Modulated Radiotherapy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVMAT: Volumetric Arc Therapy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTPS: treatment planning system\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOAR: organs at risk\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCTV: clinical target volume\u003c/p\u003e\n\u003cp\u003eUSG: ultrasound\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMRI: magnetic resonance imaging\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMWU: Mann-Whitney U\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSPSS: the Statistical Package for the Social Sciences\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eALND: axillary lymph node dissection\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: Our trial received approval from the Dokuz Eylul University Ethics Committee and was conducted in accordance with the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all participants.\u003c/p\u003e\n\u003cp\u003eConsent for publication: A consent for publication was obtained from participants\u003c/p\u003e\n\u003cp\u003eConsent for the publication of identifying images or other personal or clinical details of participants that compromise anonymity: Not Applicable\u003c/p\u003e\n\u003cp\u003eAvailability of Data and Materials: The datasets used and/or analyzed during the current study are available from the corresponding author upon\u0026nbsp;reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests: The authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003eFunding: Not applicable\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions:\u003c/p\u003e\n\u003cp\u003eSO prepared the datasets of the patients who participated in the trial, retrospectively delineated the patients\u0026rsquo; volumes, contributed to the patients\u0026rsquo; clinical assessment, and wrote the article, and was a major contributor to the manuscript.\u003c/p\u003e\n\u003cp\u003eBA contributed to patient selection, contour evaluation, contracture assessment, patients\u0026apos; clinical examination, scoring the degree of contracture, article writing, and review.\u003c/p\u003e\n\u003cp\u003eAIS was responsible for the surgery and the patient\u0026apos;s clinical examination and follow-up.\u003c/p\u003e\n\u003cp\u003eHE was responsible for statistical analysis\u003c/p\u003e\n\u003cp\u003eIBA was responsible for evaluating the radiological images and scoring of capsular contracture\u003c/p\u003e\n\u003cp\u003eIG was responsible for the article review and patient\u0026apos;s examination\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: Not applicable\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; information (optional)\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Wagle NS, Jemal A. 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Epub 2021 Jul 13. PMID: 34526867; PMCID: PMC8432999.\u003c/li\u003e\n\u003cli\u003eLiu, S., Lachapelle, J., Leung, S. \u003cem\u003eet al.\u003c/em\u003e CD8\u003csup\u003e+\u003c/sup\u003e lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. \u003cem\u003eBreast Cancer Res\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, R48 (2012). https://doi.org/10.1186/bcr3148\u003c/li\u003e\n\u003cli\u003eSahar M.A. Mahmoud et al. Tumor-Infiltrating CD8\u003csup\u003e+\u003c/sup\u003e Lymphocytes Predict Clinical Outcome in Breast Cancer. \u003cem\u003eJ Clin Oncol\u003c/em\u003e \u003cstrong\u003e29\u003c/strong\u003e, 1949-1955(2011), DOI:10.1200/JCO.2010.30.5037\u003c/li\u003e\n\u003cli\u003eLee, J., Lee, H., Jeon, S., Kim, D., Lee, Y., Bae, S., Park, W., Yoon, C., \u0026amp; Choi, J. (2025). Impact of Chemotherapy on Implant-Based Breast Reconstruction in Breast Cancer Patients: A Nationwide, Retrospective, Cohort Study. Cancers, 17. https://doi.org/10.3390/cancers17122053\u003c/li\u003e\n\u003cli\u003eNaoum GE, Salama L, Ho A, Horick NK, Oladeru O, Abouegylah M, Daniell K, MacDonald S, Arafat WO, Smith BL, Colwell AS, Taghian AG. The Impact of Chest Wall Boost on Reconstruction Complications and Local Control in Patients Treated for Breast Cancer. Int J Radiat Oncol Biol Phys. 2019 Sep 1;105(1):155-164. doi: 10.1016/j.ijrobp.2019.04.027. Epub 2019 May 2. PMID: 31055108.\u003c/li\u003e\n\u003cli\u003eSobti, N., Weitzman, R., Nealon, K., Jimenez, R., Gfrerer, L., Mattos, D., Ehrlichman, R., Gadd, M., Specht, M., Austen, W., \u0026amp; Liao, E. (2020). Evaluation of capsular contracture following immediate prepectoral versus subpectoral direct-to-implant breast reconstruction. \u003cem\u003eScientific Reports\u003c/em\u003e, 10. https://doi.org/10.1038/s41598-020-58094-4.\u003c/li\u003e\n\u003cli\u003eKobraei EM, Cauley R, Gadd M, Austen WG Jr, Liao EC. Avoiding Breast Animation Deformity with Pectoralis-Sparing Subcutaneous Direct-to-Implant Breast Reconstruction. Plast Reconstr Surg Glob Open. 2016 May 27;4(5):e708. doi: 10.1097/GOX.0000000000000681. PMID: 27579232; PMCID: PMC4995704.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Radiotherapy, Implant, Capsular contracture, Dosimetric factors ","lastPublishedDoi":"10.21203/rs.3.rs-8560553/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8560553/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e\u003cbr\u003e\nIn reconstructed breast cancer (RBC) patients, capsular contracture (CC) after radiotherapy (RT) can cause significant cosmetic issues and reduce quality of life. This study aimed to investigate CC incidence and associated risk factors at our center.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003cbr\u003e\nOur retrospective study analyzed data from all RBC patients who received RT from June 2014 to January 2025. Chi-square and Fisher’s exact tests were used for categorical variables. Since continuous variables were not normally distributed, the Mann-Whitney U test (MWU) was employed. ROC analysis identified cutoff values for significant variables.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003cbr\u003e\nA total of 47 implants in 45 patients were analyzed. The median age was 42 (26-57), with a median follow-up of 41 months (5–95). Thirty patients (63.8%) received a permanent prosthesis; 17 (36.2%) had an expander then a prosthesis. Four patients (8.5%) were treated with boost and bolus in 10 (21.3%) cases. Capsular contracture occurred in 8 patients (17%), mainly within 18 months, with 62% being Baker grade 4. No significant relationship was found between CC and categorical variants (all p\u0026gt;0.05). The Dmean of the posterior implant edge (PMI) (p=0.005) and D2% dose (p=0.039) were significantly associated with CC. ROC analysis showed the PMI Dmean had the highest discriminative power (AUROC=0.817), with a cutoff of 5024.5 cGy (75% sensitivity, 94.9% specificity). The PMI D2% dose cutoff was 5265 cGy (62.5% sensitivity, 79.5% specificity).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003cbr\u003e\nIn this study, the PMI Dmean and D2% doses were found to be associated with CC. These findings should be validated in larger studies involving a greater number of patients.\u003c/p\u003e","manuscriptTitle":"The Incidence and Dosimetric Risk Factors of Capsular Contracture in Implant-Based Breast Reconstruction Following Post-Mastectomy Radiotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-10 14:35:00","doi":"10.21203/rs.3.rs-8560553/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-02-25T01:19:17+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-31T08:32:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"285283834086292101457026349416677938379","date":"2026-01-31T08:02:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"254512583639225187515423178920721686582","date":"2026-01-29T09:34:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-29T04:22:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-29T04:20:38+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-12T12:27:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-12T11:10:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-01-12T10:59:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1b656171-f8c5-47d8-9918-f333d4ec6ec0","owner":[],"postedDate":"February 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-10T14:35:00+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-10 14:35:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8560553","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8560553","identity":"rs-8560553","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}