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Target volume contouring for radiation therapy is considered significantly more challenging than the normal organ segmentation tasks as it necessitates the utilization of both image and text-based clinical information. Inspired by the recent advancement of large language models (LLMs) that can facilitate the integration of the textural information and images, here we present an LLM-driven multimodal artificial intelligence (AI), namely LLMSeg, that utilizes the clinical information and is applicable to the challenging task of 3-dimensional context-aware target volume delineation for radiation oncology. We validate our proposed LLMSeg within the context of breast cancer radiotherapy using external validation and data-insufficient environments, which attributes highly conducive to real-world applications. We demonstrate that the proposed multimodal LLMSeg exhibits markedly improved performance compared to conventional unimodal AI models, particularly exhibiting robust generalization performance and data-efficiency., (© 2024. The Author(s).)

Purpose: This study evaluated the impact and clinical utility of an auto-contouring system for radiation therapy treatments., Methods and Materials: The auto-contouring system was implemented in 2019. We evaluated data from 2428 patients who underwent adjuvant breast radiation therapy before and after the system's introduction. We collected the treatment's finalized contours, which were reviewed and revised by a multidisciplinary team. After implementation, the treatment contours underwent a finalization process that involved manual review and adjustment of the initial auto-contours. For the preimplementation group (n = 369), auto-contours were generated retrospectively. We compared the auto-contours and final contours using the Dice similarity coefficient (DSC) and the 95% Hausdorff distance (HD95)., Results: We analyzed 22,215 structures from final and corresponding auto-contours. The final contours were generally larger, encompassing more slices in the superior or inferior directions. Among organs at risk (OAR), the heart, esophagus, spinal cord, and contralateral breast demonstrated significantly increased DSC and decreased HD95 postimplementation (all P < .05), except for the lungs, which presented inaccurate segmentation. Among target volumes, CTVn&#95;L2, L3, L4, and the internal mammary node showed increased DSC and decreased HD95 postimplementation (all P < .05), although the increase was less pronounced than the OAR outcomes. The analysis also covered factors contributing to significant differences, pattern identification, and outlier detection., Conclusions: In our study, the adoption of an auto-contouring system was associated with an increased reliance on automated settings, underscoring its utility and the potential risk of automation bias. Given these findings, we underscore the importance of considering the integration of stringent risk assessments and quality management strategies as a precautionary measure for the optimal use of such systems., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: Cardiovascular disease (CVD) remain one of the leading causes of mortality in breast cancer survivors. This study aimed to investigate the association between body composition and subsequent CVD in breast cancer survivors., Methods and Results: A retrospective cohort study of more than 70 thousand 5-year breast cancer survivors aged 40 years or older was conducted using data from the National Health Insurance Service of South Korea. Based on the percentage of predicted lean body mass (pLBMP), appendicular skeletal muscle mass (pASMP), and body fat mass (pBFMP), which were calculated using prediction equations with anthropometric data and health habits, groups were equally divided into quartiles. The risk of CVD was evaluated using multivariate Cox proportional hazards regression. Compared to those with the lowest pLBMP and pASMP, those with the highest pLBMP and pASMP had a 38% and 42% lower risk of CVD, respectively. In contrast, those with the highest pBFMP had a 57% higher risk of CVD compared to those with the lowest pBFMP. Each 1 % increase in pLBMP and pASMP was associated with a decreased risk of CVD [pLBMP, adjusted hazard ratio (aHR): 0.96, 95% CI 0.94-0.98, p < 0.05; pASMP, aHR: 0.91, 95% CI 0.87-0.95, p < 0.05] while each 1 % increase in pBFMP was associated with the increased risk of CVD (aHR: 1.05, 95% CI 1.03-1.07, p < 0.01)., Conclusion: In this cohort study, a high pLBMP, a high pASMP, and a low pBFMP were associated with a lower risk of CVD., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Purpose: Although patients with metastatic breast cancer (MBC) have been living longer with the advent of more effective treatments such as targeted therapy and immunotherapy, the disease remains incurable, and most patients will undergo therapy indefinitely. When beginning therapy, patients are typically prescribed dose often based upon the maximum tolerated dose identified in phase I clinical trials. However, patients' perspectives about tolerability and willingness to discuss individualized dosing of drugs upon initiation of a new regimen and throughout the course of treatment have not been comprehensively evaluated., Methods: Patient advocates and medical oncologists from the Patient-Centered Dosing Initiative (PCDI) developed a survey to ascertain the prevalence and severity of MBC patients' treatment-related side effects, the level of patient-physician communication, mitigation strategies, perception about the relative efficacy of higher versus lower doses, and willingness to discuss alternative dosing. The PCDI distributed the anonymous confidential online survey in August 2020 to individuals with self-reported MBC., Results: One thousand and two hundred twenty-one patients with MBC completed the survey. 86.1% (n = 1,051) reported experiencing at least one significant treatment-related side effect, and of these, 20.3% (n = 213) visited the emergency room/hospital and 43.2% (n = 454) missed at least one treatment. Nearly all patients with side effects (97.6%, n = 1,026) informed their doctor and 81.7% (n = 838) received assistance. Of the 556 patients given a dose reduction for side-effect mitigation, 82.6% (n = 459) reported relief. Notably, majority of patients (53.3%, n = 651) do not believe that higher dose is always more effective than lower dose, and 92.3% (n = 1,127) would be willing to discuss flexible dosing options with their physicians based upon personal characteristics to optimize quality of life., Conclusion: Given that the majority of patients with MBC experienced at least one substantial treatment-related side effect and most patients given a dose reduction reported improvement, innovative dosage-related strategies are warranted to sustain and improve patients' well-being. Patient-physician discussions in which the patient's unique attributes and circumstances are assessed upon initiation of new treatment and throughout the course of therapy may facilitate the identification of the most favorable dose for each patient, and the majority of patients would be receptive to this approach.

In breast cancer radiation therapy, minimizing radiation-related risks and toxicity is vital for improving life expectancy. Tailoring radiotherapy techniques and treatment positions can reduce radiation doses to normal organs and mitigate treatment-related toxicity. This study entailed a dosimetric comparison of six different external beam whole-breast irradiation techniques in both supine and prone positions. We selected fourteen breast cancer patients, generating six treatment plans in both positions per patient. We assessed target coverage and organs at risk (OAR) doses to evaluate the impact of treatment techniques and positions. Excess absolute risk was calculated to estimate potential secondary cancer risk in the contralateral breast, ipsilateral lung, and contralateral lung. Additionally, we analyzed the distance between the target volume and OARs (heart and ipsilateral lung) while considering the treatment position. The results indicate that prone positioning lowers lung exposure in X-ray radiotherapy. However, particle beam therapies (PBTs) significantly reduce the dose to the heart and ipsilateral lung regardless of the patient's position. Notably, negligible differences were observed between arc-delivery and static-delivery PBTs in terms of target conformity and OAR sparing. This study provides critical dosimetric evidence to facilitate informed decision-making regarding treatment techniques and positions., (© 2024. The Author(s).)

Background: Breast cancer-related lymphedema (BCRL) is a secondary lymphedema that occurs after breast cancer related treatments. BCRL develops from damage or dysfunction of the normally functioning lymphatic system due to surgery, radiation therapy, and rarely due to cancer recurrence. This nationwide, retrospective study was aimed at investigating the incidence and risk factors of BCRL using the database of the Korean National Health Insurance Service (NHIS)., Methods: Patients with newly diagnosed breast cancer who underwent breast surgery from 1 January 2017 to 31 December 2020, were recruited. The incidence was compared by four groups according to the operation type of breast cancer [breast conserving surgery (BCS) with sentinel lymph node biopsy (S), BCS with axillary lymph node dissection (A), total mastectomy (TM) with S, modified radical mastectomy (MRM)]. The incidence rates of lymphedema were calculated by the number of incident events by the total follow-up period. Cox proportional hazard regression was used to calculate the risk of incidence of lymphedema based on a patients' characteristics, breast cancer treatment, and comorbidities., Results: The final cohort of operation subjects that satisfied the inclusion criteria was 34 676. BCRL occurred in 4242 patients (12.2%), and the median follow-up period was 695.4 days. The BCRL was diagnosed in the BCS with S (8.0%), BCS with A (23.5%), TM with S (10.7%), and MRM (28.5%) with an incidence of 40.8, 132.2, 55.8, and 171.8 per 1000 person-years, respectively. Young age, obesity, chemotherapy, radiotherapy, residence in metropolitan areas, and hyperlipidemia were identified as risk factors., Conclusion: In Korea, the incidence of BCRL was found to be 12.2%, with the highest risk observed among patients who underwent MRM. Therefore, surgical oncologists should meticulously assess the appropriate surgical approach and consider providing education to patients with risk factors for BCRL, aiming to ensure effective prevention strategies., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

With the increasing use of flattening filter free (FFF) beams, it is important to evaluate the impact on the skin dose and target coverage of breast cancer treatments. This study aimed to compare skin doses of treatments using FFF and flattening filter (FF) beams for breast cancer. The study established treatment plans for left breast of an anthropomorphic phantom using Halcyon's 6-MV FFF beam and TrueBeam's 6-MV FF beam. Volumetric modulated arc therapy (VMAT) with varying numbers of arcs and intensity modulated radiation therapy (IMRT) were employed, and skin doses were measured at five points using Gafchromic EBT3 film. Each measurement was repeated three times, and averaged to reduce uncertainty. All plans were compared in terms of plan quality to ensure homogeneous target coverage. The study found that when using VMAT with two, four, and six arcs, in-field doses were 19%, 15%, and 6% higher, respectively, when using Halcyon compared to TrueBeam. Additionally, when using two arcs for VMAT, in-field doses were 10% and 15% higher compared to four and six arcs when using Halcyon. Finally, in-field dose from Halcyon using IMRT was about 1% higher than when using TrueBeam. Our research confirmed that when treating breast cancer with FFF beams, skin dose is higher than with traditional FF beams. Moreover, number of arcs used in VMAT treatment with FFF beams affects skin dose to the patient. To maintain a skin dose similar to that of FF beams when using Halcyon, it may be worth considering increasing the number of arcs., (© 2024. The Author(s).)

PIK3CA mutations occur in ∼8% of cancers, including ∼40% of HR-positive breast cancers, where the PI3K-alpha (PI3Kα)-selective inhibitor alpelisib is FDA approved in combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinically acquired resistance to PI3Kα inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies in 39 patients with advanced breast cancer developing acquired resistance to PI3Kα inhibitors, we observe that 50% of patients acquire genomic alterations within the PI3K pathway, including PTEN loss and activating AKT1 mutations. Notably, although secondary PIK3CA mutations were previously reported to increase sensitivity to PI3Kα inhibitors, we identified emergent secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Kα-selective versus pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Kα-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers., Significance: In one of the largest patient cohorts analyzed to date, this study defines the clinical landscape of acquired resistance to PI3Kα inhibitors. Genomic alterations within the PI3K pathway represent a major mode of resistance and identify a novel class of secondary PIK3CA resistance mutations that can be overcome by an allosteric PI3Kα inhibitor. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 240 . This article is featured in Selected Articles from This Issue, p. 201., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: To analyze the dosimetric and toxicity outcomes of patients treated with postoperative stereotactic partial breast irradiation (S-PBI)., Methods: We identified 799 women who underwent S-PBI at our institution between January 2016 and December 2022. The most commonly used dose-fraction and technique were 30 Gy in 5 fractions (91.7 %) and a robotic stereotactic radiation system with real-time tracking (83.7 %). The primary endpoints were dosimetric parameters and radiation-related toxicities. For comparison, a control group undergoing ultra-hypofractionated whole breast irradiation (UF-WBI, n = 468) at the same institution was selected., Results: A total of 815 breasts from 799 patients, with a median planning target volume (PTV) volume of 89.6 cm 3 , were treated with S-PBI. Treatment plans showed that the mean and maximum doses received by the PTV were 96.2 % and 104.8 % of the prescription dose, respectively. The volume of the ipsilateral breast that received 50 % of the prescription dose was 32.3 ± 8.9 %. The mean doses for the ipsilateral lung and heart were 2.5 ± 0.9 Gy and 0.65 ± 0.39 Gy, respectively. Acute toxicity occurred in 175 patients (21.5 %), predominantly of grade 1. Overall rate of late toxicity was 4 % with a median follow-up of 31.6 months. Compared to the UF-WBI group, the S-PBI group had comparably low acute toxicity (21.5 % vs. 25.2 %, p = 0.12) but significantly lower dosimetric parameters for all organs-at-risks (all p < 0.05)., Conclusion: In this large cohort, S-PBI demonstrated favorable dosimetric and toxicity profiles. Considering the reduced radiation exposure to surrounding tissues, external beam PBI with advanced techniques should at least be considered over traditional WBI-based approaches for PBI candidates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: To quantify interobserver variation (IOV) in target volume and organs-at-risk (OAR) contouring across 31 institutions in breast cancer cases and to explore the clinical utility of deep learning (DL)-based auto-contouring in reducing potential IOV., Methods and Materials: In phase 1, two breast cancer cases were randomly selected and distributed to multiple institutions for contouring six clinical target volumes (CTVs) and eight OAR. In Phase 2, auto-contour sets were generated using a previously published DL Breast segmentation model and were made available for all participants. The difference in IOV of submitted contours in phases 1 and 2 was investigated quantitatively using the Dice similarity coefficient (DSC) and Hausdorff distance (HD). The qualitative analysis involved using contour heat maps to visualize the extent and location of these variations and the required modification., Results: Over 800 pairwise comparisons were analysed for each structure in each case. Quantitative phase 2 metrics showed significant improvement in the mean DSC (from 0.69 to 0.77) and HD (from 34.9 to 17.9 mm). Quantitative analysis showed increased interobserver agreement in phase 2, specifically for CTV structures (5-19 %), leading to fewer manual adjustments. Underlying IOV differences causes were reported using a questionnaire and hierarchical clustering analysis based on the volume of CTVs., Conclusion: DL-based auto-contours improved the contour agreement for OARs and CTVs significantly, both qualitatively and quantitatively, suggesting its potential role in minimizing radiation therapy protocol deviation., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: The aim of this study was to evaluate the anxiety-reducing effects of virtual reality (VR) on patients with breast cancer undergoing adjuvant radiation therapy (RT)., Methods and Materials: This randomized controlled trial was conducted among patients with breast cancer receiving RT at a single institution. Of 196 enrolled and randomized patients, 97 were assigned to a VR explanation group (intervention) and 99 were assigned to the standard-of-care group (control). Anxiety levels were measured using the Amsterdam Preoperative Anxiety and Information Scale (APAIS) as the primary endpoint and the State-Trait Anxiety Inventory (STAI) and Linear Analogue Scale Assessment (LASA) as secondary endpoints. Knowledge of the RT procedure, patient satisfaction, and time spent for counseling were also assessed., Results: Intervention significantly reduced patient anxiety immediately, not only on the primary endpoint, APAIS, but also on the STAI and LASA anxiety scales. Specifically, in the intervention group, there were immediate reductions of 26.0%, 16.1%, and 55.8% for APAIS, STAI, and LASA, respectively, whereas in the control group, the respective reductions were 8.1%, 8.5%, and 13.7%. Among the 3 anxiety scales, long-term anxiety reduction was observed only when anxiety was measured by LASA. Subgroup analyses showed that the effect on anxiety did not differ based on the physician, baseline anxiety level, use of hormone therapy, or health literacy. The intervention also significantly improved knowledge of the RT procedure (81.9/100 vs 76.8/100; P = .006) and patient satisfaction with the explanation manner (6.56 vs 5.72; P < .001) compared with the control group., Conclusions: Immersive VR applied to the current procedure reduces anxiety during RT planning for patients with breast cancer. Further research is necessary to investigate the long-term effects of VR on anxiety., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Heart toxicity, such as major acute coronary events (ACE), following breast radiation therapy (RT) is of utmost concern. Thus, many studies have been investigating the effect of mean heart dose (MHD) and dose received in heart sub-structures on toxicity. Most studies focused on the dose thresholds in the heart and its sub-structures, while few studies adopted such computational methods as deep neural networks (DNN) and radiomics. This work aims to construct a feature-driven predictive model for ACE after breast RT., Methods: A recently proposed two-step predictive model that extracts a number of features from a deep auto-segmentation network and processes the selected features for prediction was adopted. This work refined the auto-segmenting network and feature processing algorithms to enhance performance in cardiac toxicity prediction. In the predictive model, the deep convolutional neural network (CNN) extracted features from 3D computed tomography (CT) images and dose distributions in three automatically segmented heart sub-structures, including the left anterior descending artery (LAD), right coronary artery (RCA), and left ventricle (LV). The optimal feature processing workflow for the extracted features was explored to enhance the prediction accuracy. The regions associated with toxicity were visualized using a class activation map (CAM)-based technique. Our proposed model was validated against a conventional DNN (convolutional and fully connected layers) and radiomics with a patient cohort of 84 cases, including 29 and 55 patient cases with and without ACE. Of the entire 84 cases, 12 randomly chosen cases (5 toxicity and 7 non-toxicity cases) were set aside for independent test, and the remaining 72 cases were applied to 4-fold stratified cross-validation., Results: Our predictive model outperformed the conventional DNN by 38% and 10% and radiomics-based predictive models by 9% and 10% in AUC for 4-fold cross-validations and independent test, respectively. The degree of enhancement was greater when incorporating dose information and heart sub-structures into feature extraction. The model whose inputs were CT, dose, and three sub-structures (LV, LAD, and RCA) reached 96% prediction accuracy on average and 0.94 area under the curve (AUC) on average in the cross-validation, and also achieved prediction accuracy of 83% and AUC of 0.83 in the independent test. On 10 correctly predicted cases out of 12 for the independent test, the activation maps implied that for cases of ACE toxicity, the higher intensity was more likely to be observed inside the LV., Conclusions: The proposed model characterized by modifications in model input with dose distributions and cardiac sub-structures, and serial processing of feature extraction and feature selection techniques can improve the predictive performance in ACE following breast RT., (© 2023 American Association of Physicists in Medicine.)

Purpose: To develop and test a multivariable normal tissue complication probability (NTCP) model predicting lymphedema in patients with breast cancer receiving radiation therapy., Methods and Materials: We retrospectively reviewed 1345 patients with breast cancer who received radiation therapy from 2 independent institutions. The patients were divided into a training cohort (institution A, n = 368, all treated with 3-dimensional conformal external beam radiation therapy [RT] with 2 Gy/fraction) and an external validation cohort (institution B, n = 977, treated either with 3-dimensional conformal external beam RT or with volumetric modulated RT and either with 1.8-2.0 Gy/fraction or with 2.67 Gy/fraction). Axillary-lateral thoracic vessel juncture (ALTJ) was delineated. The multivariable model was generated using dosimetric and clinical parameters. The performance of the model was comprehensively validated internally and externally., Results: During a median follow-up of 78.7 months for the entire cohort, 97 patients (7.2%) developed lymphedema. The multivariable model that took into account the number of lymph nodes dissected, as well as the volume of the ALTJ receiving a dose ≥35 Gy equivalent doses in 2-Gy fractions (ALTJ V35), showed good agreement between predicted and observed results for both internal and external validation (Hosmer-Lemeshow P value > .05). The area under the receiver operating characteristic curve (AUC) and negative log-likelihood values for the multivariable NTCP model were 0.89 and 0.19 in internal validation and 0.83 and 0.19 in external validation. In addition, the multivariable model performance was acceptable for hypofractionated regimens (AUC 0.70) and volumetric modulated arc therapy (AUC 0.69). The number of lymph nodes dissected and ALTJ V35 were found to be the most important factors influencing lymphedema after radiation therapy., Conclusions: We first developed and validated the multivariable NTCP model for the lymphedema incidence in patients with breast cancer after radiation therapy. The multivariable NTCP model showed excellent performance and robustness in predicting lymphedema in both internal and completely independent external validations. The multivariable model for lymphedema prediction was robust and reliable for different treatment modalities and fractionation regimens., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: We aimed to compare the initial and salvage brain-directed treatment and overall survival (OS) between patients with 1-4 brain metastases (BMs) and those with 5-10 from breast cancer (BC). We also organized a decision tree to select the initial whole-brain radiotherapy (WBRT) for these patients., Methods: Between 2008 and 2014, 471 patients were diagnosed with 1-10 BMs. They were divided into two groups based on the number of BM: 1-4 BMs (n = 337) and 5-10 BMs (n = 134). Median follow-up duration was 14.0 months., Results: Stereotactic radiosurgery (SRS)/fractionated stereotactic radiotherapy (FSRT) was the most common treatment modality (n = 120, 36%) in the 1-4 BMs group. In contrast, 80% (n = 107) of patients with 5-10 BMs were treated with WBRT. The median OS of the entire cohort, 1-4 BMs, and 5-10 BMs was 18.0, 20.9, and 13.9 months, respectively. In the multivariate analysis, the number of BM and WBRT were not associated with OS, whereas triple-negative BC and extracranial metastasis decreased OS. Physicians determined the initial WBRT based on four variables in the following order: number and location of BM, primary tumor control, and performance status. Salvage brain-directed treatment (n = 184), mainly SRS/FSRT (n = 109, 59%), prolonged OS by a median of 14.3 months., Conclusion: The initial brain-directed treatment differed notably according to the number of BM, which was chosen based on four clinical factors. In patients with ≤ 10 BMs, the number of BM and WBRT did not affect OS. The major salvage brain-directed treatment modality was SRS/FSRT and increased OS., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose . To address the shortcomings of current procedures for evaluating the measured-to-planned dose agreement in in vivo dosimetry (IVD), this study aimed to develop an accurate and efficient novel framework to identify the detector location placed on a patient's skin surface using a 3D camera and determine the planned dose at the same anatomical position corresponding to the detector location. Methods . Breast cancer treatment was simulated using an anthropomorphic adult female phantom (ATOM 702D; CIRS, Norfolk, VA, USA). An optically stimulated luminescent dosimeter was used for surface dose measurements (MyOSLchip, RadPro International GmbH, Germany) at six IVD points. Three-dimensional surface imaging (3DSI) of the phantom with the detector was performed in the treatment position using a 3D camera. The developed framework, iSMART, was designed to import 3DSI and treatment planning data for determining the position of the IVD detectors in the 3D treatment planning DICOM image. The clinical usefulness of iSMART was evaluated in terms of accuracy and efficiency, for comparison with the results obtained using cone-beam computed tomography (CBCT) image guidance. Results . The relative dose difference between the planned doses determined using iSMART and CBCT images displayed similar accuracies (within approximately ±2.0%) at all detector locations. The relative dose differences between the planned and measured doses at the six detector locations ranged from -4.8% to 3.1% for the CBCT images and -3.5% to 2.1% for iSMART. The total time required to read the planned doses at six detector locations averaged at 8.1 and 0.8 min for the CBCT images and iSMART, respectively. Conclusions . The proposed framework can improve the robustness of IVD analyses and aid in accurate and efficient evaluations of the measured-to-planned dose agreement., (Creative Commons Attribution license.)

Acupuncture is a potential therapy for breast cancer-related lymphedema (BCRL). Despite a recent meta-analysis on efficacy, data on acupuncture safety in BCRL are lacking. Current clinical guidelines recommend avoiding needling in the upper extremity affected by lymph node dissection. We undertook a systematic review focusing on acupuncture safety and treatment protocols in clinical trials for BCRL. Literature searches were conducted in PubMed, Ovid, CINAHL, and Cochrane library. Eight clinical trials on acupuncture for BCRL were analyzed. The Standards of Acupuncture intervention (STRICTA 2010) and Cochrane risk of bias (RoB2 2019) were applied to assess methods for acupuncture interventions within Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. Quantity and severity of adverse events (AE) were reviewed. A total of 189 subjects participated in 8 clinical trials with 2965 acupuncture treatments. No serious adverse events (SAE) were reported regardless of treatment laterality or protocol, with only a single grade 2 skin infection in 2,965 total treatments (0.034%), including 1,165 bilateral and 225 ipsilateral treatments. Our comprehensive review of clinical trials of acupuncture for BCRL demonstrated no significant adverse events in 2,965 treatments, including 1,390 in the affected limb. An approach for routine integration of acupuncture into BCRL maintenance therapy is proposed., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by International Society of Lymphology.)

Purpose: Spontaneous rib fracture (SRF) is a common late complication in treated breast cancer patients. This study evaluated the incidence and risk factors of ipsilateral SRF after radiotherapy (RT) in breast cancer patients. In addition, we identified dosimetric parameters that were significantly associated with ipsilateral SRF., Methods: We retrospectively reviewed 2204 patients with breast cancer who underwent RT between 2014 and 2016, and were followed up with bone scans. We evaluated clinical risk factors for ipsilateral SRF. Dose-volume histogram analysis was also performed for patients (n = 538) whose dosimetric data were available. All ipsilateral ribs were manually delineated, and dosimetric parameters of the ribs were converted into the equivalent dose in 2 Gy fractions (EQD2)., Results: Most of the patients with SRF (87.3%) were asymptomatic, and the remaining symptomatic patients complained of mild tenderness or chest wall discomfort; these symptoms all resolved within 6 months without any treatment. Ipsilateral SRF occurred in 14.5% of patients 3 years after RT. The median time to develop ipsilateral SRF was 15 months. In dosimetric analysis, near-maximum rib dose (D2cc) best predicted ipsilateral SRF. The cut-off value of D2cc was EQD2 52 Gy, as determined by receiver operating characteristic analysis. In multivariate analysis including dosimetric variables, D2cc EQD2 ≥ 52 Gy was the only significant risk factor for ipsilateral SRF., Conclusion: Our data demonstrated that near-maximum rib dose was the best dosimetric parameter to predict ipsilateral SRF in RT-treated breast cancer patients. In addition, our results suggest that patients who received RT with exceeding rib dose cut-off value and had ipsilateral SRF on bone scan be recommended routine follow-up without additional imaging tests., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Although radiotherapy (RT) increases the extra centrosomes of cancer cells compared to normal cells, centrosome clustering of cancer cells with amplified centrosomes ensures bipolar mitosis for cell proliferation in response to RT. Recent evidence suggests that centrosome clustering is a tumor-selective target for improving RT in breast cancer cells. However, whether centrosome de-clustering is involved in the activation of innate immunity in response to RT remains unknown. In this study, we showed that centrosome de-clustering of irradiated cancer cells modulates cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-mediated innate immunity in monocytes and macrophages after co-culture. Centrosome de-clustering intensifies mitotic abnormalities and cytosolic dsDNA in breast cancer cells in response to irradiation. Unexpectedly, centrosome de-clustering did not modulate the cGAS-STING signaling pathway in irradiated breast cancer cells. Importantly, centrosome de-clustering activated the cGAS-STING signaling pathway in human monocytes and mouse macrophages after co-culture with irradiated breast cancer cells. Thus, our data provide the first evidence that centrosome de-clustering of irradiated breast cancer cells induces innate immunity in tumor-associated immune cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Postoperative radiotherapy (PORT) could be useful for pN1 breast cancer patients who have undergone breast-conserving surgery (BCS) or mastectomy. However, the value of regional nodal irradiation (RNI) for BCS patients, and the indications for post-mastectomy radiotherapy (PMRT) for pN1 breast cancer mastectomy patients, have recently been challenged due to the absence of relevant trials in the era of modern systemic therapy. "PORT de-escalation" should be assessed in patients with pN1 breast cancer., Methods: The PORT-N1 trial is a multicenter, randomized, phase 3 clinical trial for patients with pN1 breast cancer that compares the outcomes of control [whole-breast irradiation (WBI) and RNI/PMRT] and experimental (WBI alone/no PMRT) groups. PORT-N1 aims to demonstrate non-inferiority of the experimental group by comparing 7-year disease-free survival rates with the control group. Female breast cancer patients with pT1-3 N1 status after BCS or mastectomy are eligible. Participants will be randomly assigned to the two groups in a 1:1 ratio. Randomization will be stratified by surgery type (BCS vs. mastectomy) and histologic subtype (triple-negative vs. non-triple-negative). In patients who receive mastectomy, dissection of ≥5 nodes is required when there is one positive node, and axillary lymph node dissection when there are two or three positive nodes. Patients receiving neoadjuvant chemotherapy are not eligible. RNI includes a "high-tangent" or wider irradiation field. This study will aim to recruit 1106 patients., Discussion: The PORT-N1 trial aims to verify that PORT de-escalation after BCS or mastectomy is safe for pN1 breast cancer patients in terms of oncologic outcomes and capable of reducing toxicity rates. This trial will provide information crucial for designing PORT de-escalation strategies for patients with pN1 breast cancer., Trial Registration: This trial was registered at ClinicalTrials.gov (NCT05440149) on June 30, 2022., (© 2022. The Author(s).)

Purpose: We aimed to investigate manifestations and patterns of care for patients with brain metastasis (BM) from breast cancer (BC) and compared their overall survival (OS) from 2005 through 2014 in Korea., Materials and Methods: We retrospectively reviewed 600 BC patients with BM diagnosed between 2005 and 2014. The median follow-up duration was 12.5 months. We categorized the patients into three groups according to the year when BM was initially diagnosed (group I [2005-2008], 98 patients; group II [2009-2011], 200 patients; and group III [2012-2014], 302 patients)., Results: Over time, the median age at BM diagnosis increased by 2.2 years (group I, 49.0 years; group II, 48.3 years; and group III, 51.2 years; p=0.008). The percentage of patients with extracranial metastasis was 73.5%, 83.5%, and 86.4% for group I, II, and III, respectively (p=0.011). The time interval between BC and BM was prolonged in patients with stage III primary BC (median, 2.4 to 3 years; p=0.029). As an initial brain-directed treatment, whole-brain radiotherapy alone decreased from 80.0% in 2005 to 41.1% in 2014. Meanwhile, stereotactic radiosurgery or fractionated stereotactic radiotherapy alone increased from 13.3% to 34.7% during the same period (p=0.005). The median OS for group I, II, and III was 15.6, 17.9, and 15.0 months, respectively, with no statistical significance., Conclusion: The manifestations of BM from BC and the pattern of care have changed from 2005 to 2014 in Korea. However, the OS has remained relatively unchanged over the 10 years.

Purpose: Our purpose was to investigate the interfraction and intrafraction reproducibility and practical applicability of continuous positive airway pressure (CPAP) for left breast volumetric modulated arc therapy (VMAT)., Methods and Materials: Interfraction reproducibility of the position of the heart was evaluated by measuring the heart-to-target distance on 20 planning computed tomography (CT) and 300 daily cone beam CT of 20 patients with left breast cancer treated with a 15-fraction VMAT. The dosimetric metrics of the whole heart and its substructures were compared between CPAP and free-breathing based VMAT plans. Intrafraction reproducibility was evaluated by measuring the motions of the breast target and diaphragm in 4-dimensional CT of 20 female patients with nonbreast cancer. Lastly, we analyzed the CPAP compliance data of 237 consecutive patients with left-sided breast cancer with and without internal mammary node irradiation (IMNI)., Results: The heart position was reproducible as evidenced by an absolute average heart-to-target distance error of 2.0 ± 2.0 mm. Compared with free-breathing, CPAP significantly reduced the mean heart dose and the dose to the left ventricle and left anterior descending artery. The average intrafraction position variation of the breast target was 0.5 ± 0.5, 2.5 ± 2.0, and 1.8 ± 1.4 mm in the mediolateral, craniocaudal, and anteroposterior directions, respectively. CPAP was successfully applied in 221 patients (93%), with a mean heart dose of 1.6 ± 0.7 Gy (IMNI: 2.0 Gy and no IMNI: 1.1 Gy)., Conclusions: CPAP has adequate heart-sparing capability and sufficient reproducibility in VMAT for left-sided breast cancer treatment, with a high compliance rate. Thus, CPAP is applicable in routine practice for left-sided breast cancer radiation therapy., (Copyright © 2022 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

This study is to investigate the optimal treatment option for synchronous bilateral breast cancer (SBBC) by comparing dosimetric and radiobiological parameters of intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) plans using single and dual isocenters. Twenty patients with SBBC without lymph node involvement were selected retrospectively. Four treatment plans were generated for each patient using the Eclipse treatment planning system (Varian Medical System, Palo Alto, CA, USA) following two delivery techniques with two isocenter conditions-IMRT using a single isocenter (IMRT&#95;Iso1), VMAT using a single isocenter (VMAT&#95;Iso1), IMRT using dual isocenters (IMRT&#95;Iso2), and VMAT using dual isocenters (VMAT&#95;Iso2). A dose of 42.56 Gy in 16 fractions was prescribed for the planning target volume (PTV). All plans were calculated using the Acuros XB algorithm and a photon optimizer for a 6-MV beam of a Vital Beam linear accelerator. PTV-related dosimetric parameters were analyzed. Further, the homogeneity index, conformity index, and conformation number were computed to evaluate plan quality. Dosimetric parameters were also measured for the organs at risk (OARs). In addition, the equivalent uniform dose corresponding to an equivalent dose related to a reference of 2 Gy per fraction, the tumor control probability, and the normal tissue complication probability were calculated based on the dose-volume histogram to investigate the radiobiological impact on PTV and OARs. IMRT&#95;Iso1 exhibited similar target coverage and a certain degree of dosimetric improvement in OAR sparing compared to the other techniques. It also exhibited some radiobiological improvement, albeit insignificant. Although IMRT&#95;Iso1 significantly increased monitor unit compared to VMAT&#95;Iso1, which is the best option in terms of delivery efficiency, there was only a 22% increase in delivery time. Therefore, in conclusion, IMRT&#95;Iso1, the complete treatment of which can be completed using a single setup, is the most effective method for treating SBBC., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Sirtuin 6 (SIRT6) regulation is involved in carcinogenesis. However, its role in breast cancer (BC) metastasis remains unclear. We investigated the effects of SIRT6 on protein kinase C activator- and cytokine-mediated cancer cell invasion and migration in MCF-7 and MDA-MB-231 cells and the association between SIRT6 and matrix metalloproteinase-9 (MMP-9) expression. To assess MMP-9 and SIRT6 expression in patients, protein levels in BC tissues were analyzed. MCF-7 and MDA-MB-231 cell viability was analyzed using MTT assays. SIRT6 was silenced in both cell lines and protein secretion, expression, and mRNA levels were analyzed. Transcription factor DNA activity was investigated using luciferase assays. Matrigel invasion assays were used to assess the effects of SIRT6 in both cell lines. SIRT6 and MMP-9 expression in cancer tissues was significantly higher than in paired normal breast tissues. 12-O-tetradecanoylphorbol-13-acetate (TPA) or tumor necrosis factor-α (TNF-α) increased MMP-9 expression and cell invasion and migration, but SIRT6 knockdown abolished these effects. SIRT6 overexpression additively increased TPA- and TNF-α-induced MMP-9 expression. SIRT6 knockdown suppressed the mitogen-activated protein kinase (MAPK) signaling pathway and thus TPA- and TNF-α-induced MMP-9 expression. SIRT6 silencing suppressed TPA- and TNF-α-induced nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) expressions in both cell lines, and treatment with MAPK, NF-κB, and AP-1 inhibitors reduced MMP-9 expression. The anti-invasive effects of SIRT6 in BC cells might be mediated by suppression of MAPK phosphorylation and reduction in NF-κB and AP-1 DNA activities, leading to MMP-9 downregulation, suggesting that SIRT6 modulation has the potential to target BC metastasis., (© 2022. The Author(s).)

Due to prolonged survival and the relatively young median age of patients, the quality of life (QOL) of breast cancer survivors is an important issue in Korea. We conducted an educational program for breast cancer survivors, and evaluated its impact on knowledge, QOL, and lifestyle changes. This study utilized a single-arm pretest-posttest design. Participants were tested before and after an educational program to measure changes in knowledge. To measure QOL change, we conducted a QOL survey at the time of enrollment and again 6 months later. Regarding the knowledge test, mean scores increased from 9.62 to 14.74 points following education (p < 0.001). After 6 months, 97 patients completed the QOL survey and the data were analyzed, showing significant improvements in anxiety (p = 0.021), depression (p = 0.003), functional well-being (p = 0.005), and breast cancer subscales of the Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) (p < 0.001). Additionally, the rates of adequate exercise significantly improved (p < 0.001), while rates of alcohol consumption and second cancer screening did not significantly change. One educational program session can improve patient knowledge, QOL, and psychosocial well-being, but is insufficient to achieve significant changes in health behavior., (© 2020. American Association for Cancer Education.)

Background: Adjuvant radiation therapy improves the overall survival and loco-regional control in patients with breast cancer. However, radiation-induced heart disease, which occurs after treatment from incidental radiation exposure to the cardiac organ, is an emerging challenge. This study aimed to generate synthetic contrast-enhanced computed tomography (SCECT) from non-contrast CT (NCT) using deep learning (DL) and investigate its role in contouring cardiac substructures. We also aimed to determine its applicability for a retrospective study on the substructure volume-dose relationship for predicting radiation-induced heart disease., Methods: We prepared NCT-CECT cardiac scan pairs of 59 patients. Of these, 35, 4, and 20 pairs were used for training, validation, and testing, respectively. We adopted conditional generative adversarial network as a framework to generate SCECT. SCECT was validated in the following three stages: (1) The similarity between SCECT and CECT was evaluated; (2) Manual contouring was performed on SCECT and CECT with sufficient intervals and based on this, the geometric similarity of cardiac substructures was measured between them; (3) The treatment plan was quantitatively analyzed based on the contours of SCECT and CECT., Results: While the mean values (± standard deviation) of the mean absolute error, peak signal-to-noise ratio, and structural similarity index measure between SCECT and CECT were 20.66 ± 5.29, 21.57 ± 1.85, and 0.77 ± 0.06, those were 23.95 ± 6.98, 20.67 ± 2.34, and 0.76 ± 0.07 between NCT and CECT, respectively. The Dice similarity coefficients and mean surface distance between the contours of SCECT and CECT were 0.81 ± 0.06 and 2.44 ± 0.72, respectively. The dosimetry analysis displayed error rates of 0.13 ± 0.27 Gy and 0.71 ± 1.34% for the mean heart dose and V5Gy, respectively., Conclusion: Our findings displayed the feasibility of SCECT generation from NCT and its potential for cardiac substructure delineation in patients who underwent breast radiation therapy., (© 2022. The Author(s).)

Purpose: We previously constructed a nomogram for predicting the risk of arm lymphedema following contemporary breast cancer treatment. This nomogram should be validated in patients with different background characteristics before use. Therefore, we aimed to externally validate the nomogram in a large multi-institutional cohort., Methods: Overall, 8835 patients who underwent breast cancer surgery during 2007-2017 were identified. Data of variables in the nomogram and arm lymphedema were collected. The nomogram was validated externally using C-index and integrated area under the curve (iAUC) with 1000 bootstrap samples and by calibration plots., Results: Overall, 1377 patients (15.6%) developed lymphedema. The median time from surgery to lymphedema development was 11.4 months. Lymphedema rates at 2, 3, and 5 years were 11.2%, 13.1%, and 15.6%, respectively. Patients with lymphedema had significantly higher body mass index (median, 24.1 kg/m 2 vs. 23.4 kg/m 2 ) and a greater number of removed nodes (median, 17 vs. 6) and more frequently underwent taxane-based chemotherapy (85.7% vs. 41.9%), total mastectomy (73.1% vs. 52.1%), conventionally fractionated radiotherapy (71.9% vs. 54.2%), and regional nodal irradiation (70.7% vs 22.4%) than those who did not develop lymphedema (all P < 0.001). The C-index of the nomogram was 0.7887, and iAUC was 0.7628, indicating good predictive accuracy. Calibration plots confirmed that the predicted lymphedema risks were well correlated with the actual lymphedema rates., Conclusion: This nomogram, which was developed using factors related to multimodal breast cancer treatment and was validated in a large multi-institutional cohort, can well predict the risk of breast cancer-related lymphedema., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Seroma is a common complication in prepectoral breast reconstruction. PICO TM dressing, a type of incisional negative pressure wound therapy (iNPWT), was used to reduce complications postoperatively., Methods: This study was a retrospective cohort study that included patients who underwent prepectoral breast reconstruction between February 2017 and July 2019. There were two groups: one that received PICO TM dressing and a control group. The frequencies of overall complications, major seromas, and reoperations were analyzed. The durations and total amounts of seromas were also analyzed., Result: Sixty patients were included in this study (PICO TM : 37 and non-PICO TM patients: 23). The overall incidence of complications, major seromas, and frequency of reoperations were lower in the PICO group compared to the non-PICO TM group (18.9% vs. 52.2%, p = 0.007; 16.2% vs. 43.5%, p = 0.020; 2.7% vs. 26.1%, p = 0.006, respectively). Univariate analysis was used to analyze the risk factors for complications due to the application of PICO TM dressing and showed statistically significant results for any complication. When univariate analysis was performed on risk factors for seroma, the duration of seroma showed statistical significance in association with PICO TM dressing status and mastectomy volume. The total number of patients who developed seroma was statistically correlated with age, PICO TM dressing status, and mastectomy volume., Conclusions: PICO TM dressing after prepectoral breast reconstruction could be a useful tool for reducing the frequency of complications and major seroma, as well as the duration and total incidences of seroma., Level of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Background: To assess the performance of contrast-enhanced spectral mammography (CESM) for the prediction of DCIS underestimation in comparison with mammography, breast US, and breast MRI., Patients and Methods: We prospectively enrolled patients diagnosed with DCIS on preoperative core biopsy. Visibility, lesion type, and extent on each imaging modality, CESM gray values (CGV) were evaluated. Pathologic features of core biopsy and surgery were recorded. Chi-square or Fisher's exact test were used for univariate analysis. Multivariate logistic regression analysis was used to find independent predictors for DCIS underestimation and receiver operating characteristic (ROC) curve analysis was performed., Results: A total of 113 lesions in 108 patients were analyzed (50 pure DCIS; 63 underestimated DCIS). Visibility on mammography, breast US, CESM, and breast MRI were 44%, 76%, 58%, and 80% for pure DCIS, and 73%, 81%, 86%, and 92% for underestimated DCIS. Tumor extents on surgical pathology of pure and underestimated DCIS were 1.11 ± 1.35 cm and 2.61 ± 2.09 cm. On multivariate analysis, nuclear grade and suspected invasion on core biopsy, visibility on mammography, and extent on breast MRI were independent factors for the model 1, whereas nuclear grade on core biopsy, extent on CESM, and mean CGV on MLO-recombined image were independent factors for the model 2. Area under ROC curve (AUC) was 0.843 for model 1 including breast MRI, whereas AUC was 0.823 for model 2 including CESM, which didn't show a significant difference (P = .968)., Conclusion: For detecting underestimated DCIS, CESM was superior to mammography and breast US, and comparable to breast MRI., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: We aimed to assess the real-world efficacy of nab-paclitaxel in metastatic breast cancer patients., Materials and Methods: This is a retrospective study performed in two tertiary referral hospitals in Korea. Patients with metastatic breast cancer treated with nab-paclitaxel (Abraxane®) between March 2016 and March 2020 were enrolled., Results: A total of 102 patients with metastatic breast cancer were included. Patients were heavily pre-treated with a median of four prior lines of chemotherapy (5 lines when including endocrine therapy in hormone-receptor-positive patients), and 66 patients (64.7%) were exposed to taxanes in the metastatic setting. According to St. Gallen molecular subtypes, 36 patients (35.3%) were luminal A, 28 (27.5%) were luminal B, 18 (17.7%) were human epidermal growth factor receptor 2-positive and 20 (19.6%) had triple-negative disease. Fifty patients (49.0%) were treated with a 3-weekly regimen (260 mg/m2 on day 1 every 3 weeks), and 52 (51.0%) were treated with a weekly regimen (100 mg/m2 every week). Objective response rate was 22.9%. After a median follow-up of 22.0 months, median progression-free survival (PFS) was 4.0 months (95% confidence interval [CI], 2.6 to 4.8) and median overall survival was 8.7 months (95% CI, 7.5 to 11.2). Patients treated with weekly regimen had longer PFS compared to 3-weekly regimen (5.5 vs. 2.3 months, p < 0.001). Multivariate analysis revealed the treatment regimen as an independent prognostic factor for PFS. There was no grade 3 or 4 hypersensitivity reaction., Conclusion: This real-world data shows that nab-paclitaxel is a reasonable treatment option in heavily pre-treated and/or taxane-exposed metastatic breast cancer patients.

Background: There is an increasing interest in HER2-low breast cancer with promising data from clinical trials using novel anti-HER2 antibody-drug conjugates. We explored the differences in clinicopathological characteristics and survival outcomes between HER2-low and HER2-IHC 0 breast cancer., Methods: Using nationwide data from the Korean Breast Cancer Registry between 2006 and 2011, 30,491 patients with stages I to III breast cancer were included in the analysis: 9,506 (31.2%) in the HER2-low group and 20,985 (68.8%) in the HER2-IHC 0 group. Kaplan-Meier and Cox proportional hazards regression survival analysis were used to compare breast cancer-specific survival between the two groups., Results: HER2-low breast cancer was more frequent in patients with hormone receptor-positive breast cancer than in those with triple-negative breast cancer. In patients with hormone receptor-positive breast cancer, HER2-low breast cancer was associated with fewer T4 tumors, higher histological grade, and a negative lymphatic invasion. In patients with triple-negative breast cancer, HER2-low breast cancer was associated with a high lymph node ratio and positive lymphatic invasion. HER2-low breast cancer was significantly associated with a lower Ki-67 labeling index. No significant difference was observed in overall survival between the two groups. HER2-low breast cancer showed significantly better breast cancer-specific survival than HER2-IHC 0 breast cancer, regardless of the hormone receptor status. In multivariate analysis, the impact of low HER2 expression on breast cancer-specific survival was significant only in triple-negative breast cancer (HRs, 0.68; 95% CI, 0.49-0.93; P = 0.019)., Conclusions: These findings suggest that the biology and clinical impact of low HER2 expression can differ according to the hormone receptor status and support the need for further investigation on the understanding of the biology of HER2-low breast cancer., (© 2022. The Author(s).)

Objectives: To investigate machine learning approaches for radiomics-based prediction of prognostic biomarkers and molecular subtypes of breast cancer using quantification of tumor heterogeneity and angiogenesis properties on magnetic resonance imaging (MRI)., Methods: This prospective study examined 291 invasive cancers in 288 patients who underwent breast MRI at 3 T before treatment between May 2017 and July 2019. Texture and perfusion analyses were performed and a total of 160 parameters for each cancer were extracted. Relationships between MRI parameters and prognostic biomarkers were analyzed using five machine learning algorithms. Each model was built using only texture features, only perfusion features, or both. Model performance was compared using the area under the receiver-operating characteristic curve (AUC) and the DeLong method, and the importance of MRI parameters in prediction was derived., Results: Texture parameters were associated with the status of hormone receptors, human epidermal growth factor receptor 2, and Ki67, tumor size, grade, and molecular subtypes (p < 0.002). Perfusion parameters were associated with the status of hormone receptors and Ki67, grade, and molecular subtypes (p < 0.003). The random forest model integrating texture and perfusion parameters showed the highest performance (AUC = 0.75). The performance of the random forest model was the best with a special scale filter of 0 (AUC = 0.80). The important parameters for prediction were texture irregularity (entropy) and relative extracellular extravascular space (V e )., Conclusions: Radiomic machine learning that integrates tumor heterogeneity and angiogenesis properties on MRI has the potential to noninvasively predict prognostic factors of breast cancer., Key Points: • Machine learning, integrating tumor heterogeneity and angiogenesis properties on MRI, can be applied to predict prognostic biomarkers and molecular subtypes in breast cancer. • The random forest model showed the best predictive performance among the five machine learning models (logistic regression, decision tree, naïve Bayes, random forest, and artificial neural network). • The most important MRI parameters for predicting prognostic factors in breast cancer were texture irregularity (entropy) among texture parameters and relative extracellular extravascular space (V e ) among perfusion parameters., (© 2021. European Society of Radiology.)

Background: To investigate outcomes of salvage whole-brain radiotherapy (WBRT) for recurrent brain metastases (BM) from breast cancer (BC), to identify prognostic factors of overall survival (OS), and to propose a novel prognostic classification for OS in these patients., Materials and Methods: We identified 54 patients who had received salvage WBRT as the second brain-focused treatment for recurrent BM from BC (2000-2014). The median follow-up duration was 4.9 months. A recursive partitioning analysis (RPA) was conducted to develop a model to predict OS at the time of salvage WBRT., Results: The median OS was 6.8 months. OS according to BC-specific graded prognostic assessment (breast-GPA), modified breast-GPA, and updated breast-GPA did not represent our cohort. In the multivariate analysis, a long time before salvage WBRT (≥16 months), control of primary BC or extracranial metastases, systemic treatment after salvage WBRT, and administration of a biologically effective dose for an α/β of 10 Gy (BED10) of salvage WBRT >37.5 Gy showed superior OS. We proposed three RPA classes based on the control of both primary BC and extracranial metastasis and BED10 of salvage WBRT: class I, class II, and class III. In this model, patients with class I experienced the best OS (34.6 months; class II, 5.0 months; class III, 2.4 months; P < 0.001)., Conclusions: In our RPA classification according to the control of both primary BC and extracranial metastasis and the dose of salvage WBRT, significant differences in OS were observed. The subsequent use of a systemic treatment showed better OS., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In the recent trend toward less aggressive approaches to breast reconstruction, minimally invasive harvesting of the latissimus dorsi (LD) flaps has long been a desirable goal. Endoscopically-assisted LD flap harvesting was reported as a method for minimizing scar formation and reducing donor-site morbidity. This study investigates the surgical outcomes of endoscopically-assisted immediate breast reconstruction with LD muscle flaps., Materials and Methods: This prospective study included 21 patients who underwent endoscopically-assisted breast reconstruction with LD muscle flap and 20 patients who underwent breast reconstruction with conventional harvesting LD musculocutaneous flap. In patients with nonexcised skin or possible primary closure, the reconstruction was performed with endoscopically-assisted LD muscle flaps using the single-port and CO 2 gas insufflation technique. The patients were classified into groups according to the location of the defect and mastectomy type. Moreover, patient satisfaction was investigated 6 months after surgery., Results: In patients who underwent endoscopically-assisted breast reconstruction with LD muscle flaps, the scar of the donor-site was vertical, and the size was 4 cm to be obscured when lowering the arms. In comparison with patients who underwent breast reconstruction with conventional LD flaps, those who underwent endoscopically-assisted breast reconstruction with LD muscle flaps showed shorter hospital stay and no difference in patient satisfaction., Conclusion: Endoscopically-assisted breast reconstruction with LD flaps showed no difference in patient satisfaction with good esthetic results compared with conventional LD flaps. The endoscopic LD muscle flap harvest technique using a single-port and CO2 insufflation technique can be very useful in breast reconstruction that does not require a skin paddle., Level of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Objectives: To evaluate the oncologic outcomes and risk factors for locoregional recurrence (LRR) and nipple-areola complex recurrence (NR) in a large series of breast cancer patients who underwent nipple-sparing mastectomy (NSM) and immediate reconstruction after neoadjuvant chemotherapy (NACT)., Summary of Background Data: The use of NSM and immediate reconstruction in breast cancer patients receiving NACT is increasing. However, the oncologic safety of this approach is unclear., Patients and Methods: A total of 310 breast cancer patients (319 breasts) who underwent NACT and NSM between February 2010 and November 2016 were retrospectively analyzed. Clinical and pathologic factors associated with increased risks of LRR and NR were analyzed using univariate (Chi-square or Fisher exact test) and multivariate (Cox proportional hazard regression model) analyses., Results: During a mean follow-up of 63 ± 22 months, 38 cases had LRR as the first event, including 6 cases of NR as the first event. The 5-year cumulative LRR and NR rates were 11.0% and 1.9%, respectively. In univariate analysis, clinical T stage, pathologic nodal status, histologic grade, lymphovascular invasion, and post-NACT Ki67 status were associated with increased LRR risk, and post-NACT Ki67 status was the only significant risk factor for NR. In multivariate analysis, post-NACT Ki67 ≥10% (hazard ratio, 4.245; 95% confidence interval, 1.865-9.663; P = 0.001) was an independent risk factor for LRR., Conclusions: NSM and immediate reconstruction seem to be oncologically safe with acceptable LRR and NR rates for appropriately selected breast cancer patients treated with NACT. Post-NACT Ki67 ≥10% was associated with increased risk of LRR or NR, and therefore, necessitates cautious follow-up., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Matriptases, members of the type II transmembrane serine protease family, are cell surface proteolytic enzymes that mediate tumor invasion and metastasis. Matriptase is highly expressed in breast cancer and is associated with poor patient outcome. However, the cellular mechanism by which matriptase mediates breast cancer invasion remains unknown. The present study aimed to determine the role of matriptase in the protein kinase C (PKC)‑mediated metastasis of MCF‑7 human breast cancer cells. Matriptase small interfering RNA‑mediated knockdown significantly attenuated the 12‑ O ‑tetradecanoylphorbol‑13‑acetate (TPA)‑induced invasiveness and migration of MCF‑7 cells, and inhibited the activation of phospholipase C γ2 (PLCγ2)/PKC/MAPK signaling pathways. Matriptase‑knockdown also suppressed the expression of MMP‑9 and inhibited the activation of NF‑κB/activator protein‑1 in MCF‑7 cells. Additionally, GB83 [an inhibitor of protease‑activated receptor‑2 (PAR‑2)] inhibited PKC‑mediated MMP‑9 expression and metastatic ability in MCF‑7 cells. Furthermore, downregulation of matriptase suppressed TPA‑induced MMP‑9 expression and invasiveness via PAR‑2/PLCγ2/PKC/MAPK activation. These findings shed light on the mechanism underlying the role of matriptase in MCF‑7 cell invasion and migration ability, and suggest that matriptase modulation could be a promising therapeutic strategy for preventing breast cancer metastasis.

Purpose: To study the performance of a proposed deep learning-based autocontouring system in delineating organs at risk (OARs) in breast radiotherapy with a group of experts., Methods: Eleven experts from two institutions delineated nine OARs in 10 cases of adjuvant radiotherapy after breast-conserving surgery. Autocontours were then provided to the experts for correction. Overall, 110 manual contours, 110 corrected autocontours, and 10 autocontours of each type of OAR were analyzed. The Dice similarity coefficient (DSC) and Hausdorff distance (HD) were used to compare the degree of agreement between the best manual contour (chosen by an independent expert committee) and each autocontour, corrected autocontour, and manual contour. Higher DSCs and lower HDs indicated a better geometric overlap. The amount of time reduction using the autocontouring system was examined. User satisfaction was evaluated using a survey., Results: Manual contours, corrected autocontours, and autocontours had a similar accuracy in the average DSC value (0.88 vs. 0.90 vs. 0.90). The accuracy of autocontours ranked the second place, based on DSCs, and the first place, based on HDs among the manual contours. Interphysician variations among the experts were reduced in corrected autocontours, compared to variations in manual contours (DSC: 0.89-0.90 vs. 0.87-0.90; HD: 4.3-5.8 mm vs. 5.3-7.6 mm). Among the manual delineations, the breast contours had the largest variations, which improved most significantly with the autocontouring system. The total mean times for nine OARs were 37 min for manual contours and 6 min for corrected autocontours. The results of the survey revealed good user satisfaction., Conclusions: The autocontouring system had a similar performance in OARs as that of the experts' manual contouring. This system can be valuable in improving the quality of breast radiotherapy and reducing interphysician variability in clinical practice., (© 2021. The Author(s).)

Purpose: To study the hypothyroidism risk after adjuvant radiation therapy (RT) and the association of different RT targets with hypothyroidism risk., Methods: We studied 4073 women treated with adjuvant RT for breast cancer from 2007 to 2016. The primary endpoint was hypothyroidism development after RT. Patients were divided and analyzed into 3 groups: whole breast (WB)-alone (n = 2468), regional node irradiation (RNI)-Lv.4 (n = 215; cranial border at the subclavian artery, according to the European Society for Radiotherapy and Oncology consensus guideline), and RNI-supraclavicular lymph node (SCL) (n = 1390; cranial border at the cricoid cartilage). In general, RNI-Lv.4 was used in the patients with high-risk pN0 and pN1 breast cancer. In auxiliary analysis, the mean thyroid dose was estimated in each group (total n = 600, 200 from each group). All the doses were converted to the equivalent dose in 2 Gy fractions (EQD2) with α/β ratios of 3., Results: The median follow-up duration was 84 months (WB-alone, 84 months; RNI-Lv.4, 44 months; RNI-SCL, 91 months). The 3-year hypothyroidism incidence rate differed significantly between the RNI-SCL and WB-alone groups (2.2% vs 0.8%; Bonferroni corrected P [Pc] < .001) but not between the RNI-Lv.4 and WB-alone groups (0.9% vs 0.8%; Pc > .05). The Cox model revealed an adjusted hazard ratio of 2.25 (95% CI, 1.49-3.38) for RNI-SCL vs WB-alone, 1.69 (95% CI, 1.12-2.56) for adjuvant systemic therapies, and 2.07 (95% CI, 1.07-3.99) for age <60 years. In the subgroup analysis, the hypothyroidism risk became more prominent in patients aged <60 years. The mean exposure doses to the thyroid were 0.23 versus 1.93 versus 7.89 Gy (EQD2) for the WB-alone versus RNI-Lv.4 versus RNI-SCL groups (P < .001). No statistically different locoregional recurrence rates were seen between groups (5-year rate: <3%)., Conclusions: The risk of hypothyroidism increases after RNI-SCL for breast cancer but not after RNI-Lv 4. These data support routine contouring of the thyroid in the RNI setting, and future studies are required to develop optimal dose-volume constraints., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Survival of breast cancer patients has improved, and treatment-related changes regarding metabolic profile deterioration after neoadjuvant systemic treatment (NST) become important issues in cancer survivors. We sought to compare metabolic profile changes and the neutrophil-to-lymphocyte ratio (NLR) between patients undergoing neoadjuvant chemotherapy (NCT) and neoadjuvant endocrine therapy (NET) 3 years after the treatment. In a prospective, randomized, phase III trial which compared 24 weeks of NCT with adriamycin and cyclophosphamide followed by docetaxel and NET with goserelin and tamoxifen (NEST), 123 patients in the Asan Medical Center were retrospectively reviewed to evaluate metabolic changes, such as body mass index (BMI), blood pressure (BP), total cholesterol (TC), fasting glucose, and the NLR. The mean age of patients was 42 years. The changes in BMI, serum glucose, and TC during NST and after 3 years were significantly different between NCT and NET. The proportion of overweight + obese group and the mean BMI were significantly increased during NCT (26.6% to 37.5%, 22.84 kg/m 2 to 23.87 kg/m 2 , p < 0.05), and these attributes found to have normalized at the 3-year follow-up. In the NET group, BMI changes were not observed (p > 0.05, all). There were no differences in changes over time among in the Hypertension group during NCT and NET (p = 0.96). The mean value of serum TC and fasting glucose significantly increased (< 0.05, both) during NCT and decreased 3 years after NCT (p < 0.05); however, no significant changes were observed in the NET group. The NLR was increased from 1.83 to 3.18 after NCT (p < 0.05) and decreased from 1.98 to 1.43 (p < 0.05) after NET. Compared with minimal metabolic effect of NET, NCT worsens metabolic profiles, which were recovered over 3 years. The NLR was increased after NCT but decreased after NET.

Bruton's agammaglobulinemia tyrosine kinase (BTK) is an important cytoplasmic tyrosine kinase involved in B‑lymphocyte development, differentiation, and signaling. Activated protein kinase C (PKC), in turn, induces the activation of mitogen‑activated protein kinase (MAPK) signaling, which promotes cell proliferation, viability, apoptosis, and metastasis. This effect is associated with nuclear factor‑κB (NF‑κB) activation, suggesting an anti‑metastatic effect of BTK inhibitors on MCF‑7 cells that leads to the downregulation of matrix metalloproteinase (MMP)‑9 expression. However, the effect of BTK on breast cancer metastasis is unknown. In this study, the anti‑metastatic activity of BTK inhibitors was examined in MCF‑7 cells focusing on MMP‑9 expression in 12‑ O ‑tetradecanoylphorbol‑13‑acetate (TPA)‑stimulated MCF‑7 cells. The expression and activity of MMP‑9 in MCF‑7 cells were investigated using quantitative polymerase chain reaction analysis, western blotting, and zymography. Cell invasion and migration were investigated using the Matrigel invasion and cell migration assays. BTK inhibitors [ibrutinib (10 µM), CNX‑774 (10 µM)] significantly attenuated TPA‑induced cell invasion and migration in MCF‑7 cells and inhibited the activation of the phospholipase Cγ2/PKCβ signaling pathways. In addition, small interfering RNA specific for BTK suppressed MMP‑9 expression and cell metastasis. Collectively, results of the present study indicated that BTK suppressed TPA‑induced MMP‑9 expression and cell invasion/migration by activating the MAPK or IκB kinase/NF‑κB/activator protein‑1 pathway. The results clarify the mechanism of action of BTK in cancer cell metastasis by regulating MMP‑9 expression in MCF‑7 cells.

Purpose: To identify the risk factors leading to new brain metastases (BM) following brain-directed treatment for initial BM resulting from breast cancer (BC)., Methods: In this multi-institutional study, 538 BC patients with available follow-up imaging after brain-directed treatment for initial BM were analyzed. Tumor molecular subtypes were classified as follows: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-, n = 136), HER2-positive (HER2+, n = 253), or triple-negative BC (TNBC, n = 149)., Results: In 37.4% of patients, new BM emerged at a median of 10.5 months after brain-directed treatment for initial BM. The 1-year actuarial rate of new BM for HR+/HER2-, HER2+, and TNBC were 51.9%, 44.0%, and 69.6%, respectively (p = 0.008). Initial whole-brain radiotherapy (WBRT) reduced new BM rates (22.5% reduction at 1 year, p < 0.001) according to molecular subtype (HR+/HER2-, 42% reduction at 1 year, p < 0.001; HER2+, 18.5%, p = 0.004; TNBC, 16.9%, p = 0.071). Multivariate analysis revealed an increased risk of new BM for the following factors: shorter intervals between primary BC diagnoses and BM (p = 0.031); TNBC (relative to HR+/HER2-) (p = 0.016); presence of extracranial metastases (p = 0.019); number of BM (>4) (p < 0.001); and BM in both tentorial regions (p = 0.045). Anti-HER2 therapy in HER2+ patients (p = 0.013) and initial use of WBRT (p < 0.001) significantly lowered new BM development., Conclusions: Tumor molecular subtypes were associated with both rates of new BM development and the effectiveness of initial WBRT. Anti-HER2 therapy in HER2+ patients significantly lowered new BM occurrence.

Background: In breast cancer patients receiving radiotherapy (RT), accurate target delineation and reduction of radiation doses to the nearby normal organs is important. However, manual clinical target volume (CTV) and organs-at-risk (OARs) segmentation for treatment planning increases physicians' workload and inter-physician variability considerably. In this study, we evaluated the potential benefits of deep learning-based auto-segmented contours by comparing them to manually delineated contours for breast cancer patients., Methods: CTVs for bilateral breasts, regional lymph nodes, and OARs (including the heart, lungs, esophagus, spinal cord, and thyroid) were manually delineated on planning computed tomography scans of 111 breast cancer patients who received breast-conserving surgery. Subsequently, a two-stage convolutional neural network algorithm was used. Quantitative metrics, including the Dice similarity coefficient (DSC) and 95% Hausdorff distance, and qualitative scoring by two panels from 10 institutions were used for analysis. Inter-observer variability and delineation time were assessed; furthermore, dose-volume histograms and dosimetric parameters were also analyzed using another set of patient data., Results: The correlation between the auto-segmented and manual contours was acceptable for OARs, with a mean DSC higher than 0.80 for all OARs. In addition, the CTVs showed favorable results, with mean DSCs higher than 0.70 for all breast and regional lymph node CTVs. Furthermore, qualitative subjective scoring showed that the results were acceptable for all CTVs and OARs, with a median score of at least 8 (possible range: 0-10) for (1) the differences between manual and auto-segmented contours and (2) the extent to which auto-segmentation would assist physicians in clinical practice. The differences in dosimetric parameters between the auto-segmented and manual contours were minimal., Conclusions: The feasibility of deep learning-based auto-segmentation in breast RT planning was demonstrated. Although deep learning-based auto-segmentation cannot be a substitute for radiation oncologists, it is a useful tool with excellent potential in assisting radiation oncologists in the future. Trial registration Retrospectively registered.

Background: Spontaneous rib fractures (SRFs) are defined as fractures without apparent blunt force trauma. This study evaluated the incidence and risk factors of SRFs after treatment of patients with breast cancer based on bone scans. In addition, we analyzed radiation-associated SRFs and identified radiotherapy (RT) factors related to SRF., Patients and Methods: We retrospectively reviewed 1265 patients with breast cancer who underwent surgery in 2015 at our institution, and were followed-up with at least 3 bone scans. Bone scans were conducted approximately every 12 months after breast cancer treatment. The endpoint was SRF detected by bone scan. In this study, 754 (60%) patients were treated with chemotherapy, 867 (69%) with RT, and 946 (75%) with anti-hormone therapy., Results: The median follow-up duration was 37.5 months. A total of 209 (16.5%) patients experienced SRFs during follow-up. The incidence of SRFs increased sharply during the 3-year follow-up period after completion of treatment. In multivariate analyses, abnormal bone density, chemotherapy, and RT were significant risk factors for SRFs. In patients treated with RT (n = 867), 159 (18%) rib fractures occurred: 127 (80%) in the ipsilateral breast and 32 (20%) in the contralateral breast. Among the patients with ipsilateral SRFs who received tumor bed boost (n = 84), the SRF occurred inside the boost field in 80 (95%) cases. Multivariate analysis of RT subgroups showed that hypofractionated RT increased the rate of SRFs (P = .002)., Conclusions: Most of the rib fractures that occurred after treatment were spontaneous. Hypofractionated RT increased the risk of ipsilateral rib fractures in RT-treated patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The three-dimensional field-in-field (3-D FIF) technique for radiotherapy is an advanced, state-of-the-art method that uses multileaf collimators to generate a homogeneous and conformal dose distribution via segmental subfields. The purpose of this study is to evaluate the dosimetric reproducibility of 3-D FIF plans using the original simulation computed tomography (iCT) scans and re-simulation CT (rCT) scans for whole breast irradiation (WBI) schedule. This study enrolled a total of 34 patients. The study population underwent iCT scans for standard WBI and took rCT scans after 45 Gy of WBI for cone down boost plans. The dosimetric parameters (V 105% , V 103% , V 100% , V 98% , V 95% , V 90% , V 50% ), plan quality indices (conformity index, homogeneity index) and clinical parameters (isocenter-breast axis, isocenter-lung axis, soft tissue volumes within radiation field, lung volumes within radiation field) were assessed. The median time interval from surgery to iCT was 33 days and from iCT to rCT was 35 days. All dosimetric parameters exhibited statistically significant differences between iCT and rCT among cohorts with a surgery-iCT interval of < 60 days. Homogeneity index showed a statistically significant increase from iCT to rCT among all cohorts. Soft tissue volumes (p = 0.001) and isocenter-breast axis (p = 0.032) exhibited statistically significant differences among cohorts with surgery-iCT interval < 60 days. Regarding the reproducibility of the 3-D FIF WBI plans, significant changes were observed in dosimetric and clinical factors, particularly in study cohorts with a surgery-simulation interval < 60 days. The main contributing factor of these transitions seemed to be the changes in volume of the soft tissue within the WBI field. Further confirmative studies are necessary to determine the most suitable timing and technique for WBI.

Purpose: The purpose of this study was to examine the effects of 24 wk of functional impact training (FIT) that consisted of resistance and high-impact exercises in comparison with yin yoga on body composition, bone mineral density (BMD), blood biomarkers for bone metabolism, and strength in breast cancer survivors (BCS)., Methods: Forty-four BCS (60.3 ± 8.3 yr) were randomly assigned to the FIT or yin yoga group. Body composition and BMD were measured via dual energy x-ray absorptiometry. Blood biomarkers for bone metabolism were analyzed via enzyme-linked immunosorbent assays. Upper and lower body strength was assessed using a one-repetition maximum chest press and isokinetic knee extension/flexion using the Biodex System 3, respectively. Participants completed 45-min FIT or yin yoga sessions twice weekly for 24 wk. Changes in dependent variables over time were analyzed using repeated-measures ANOVA. Significance was accepted at P ≤ 0.05., Results: There were no group-time effects for body composition, BMD, or blood biomarkers. Main effects were observed for left femoral neck (0.883 ± 0.138 to 0.870 ± 0.131 g·cm) and left forearm (0.465 ± 0.078 to 0.457 ± 0.069 g·cm) BMD. The FIT group improved upper body strength (73.2 ± 18.1 to 83.2 ± 22.3 kg), whereas the yin yoga group did not (59.8 ± 14.8 to 59.3 ± 15.6 kg). Main time effects were observed for peak isokinetic knee extension and flexion at all speeds with an average improvement of 13.2% and 16.2%, respectively., Conclusion: Both FIT and yin yoga may be beneficial exercise modes for improving lower body strength, although only FIT improved upper body strength. Additional research is needed to examine the effectiveness of FIT programs of longer duration and/or higher intensity on body composition and BMD in BCS.

Manual segmentation is the gold standard method for radiation therapy planning; however, it is time-consuming and prone to inter- and intra-observer variation, giving rise to interests in auto-segmentation methods. We evaluated the feasibility of deep learning-based auto-segmentation (DLBAS) in comparison to commercially available atlas-based segmentation solutions (ABAS) for breast cancer radiation therapy. This study used contrast-enhanced planning computed tomography scans from 62 patients with breast cancer who underwent breast-conservation surgery. Contours of target volumes (CTVs), organs, and heart substructures were generated using two commercial ABAS solutions and DLBAS using fully convolutional DenseNet. The accuracy of the segmentation was assessed using 14 test patients using the Dice Similarity Coefficient and Hausdorff Distance referencing the expert contours. A sensitivity analysis was performed using non-contrast planning CT from 14 additional patients. Compared to ABAS, the proposed DLBAS model yielded more consistent results and the highest average Dice Similarity Coefficient values and lowest Hausdorff Distances, especially for CTVs and the substructures of the heart. ABAS showed limited performance in soft-tissue-based regions, such as the esophagus, cardiac arteries, and smaller CTVs. The results of sensitivity analysis between contrast and non-contrast CT test sets showed little difference in the performance of DLBAS and conversely, a large discrepancy for ABAS. The proposed DLBAS algorithm was more consistent and robust in its performance than ABAS across the majority of structures when examining both CTVs and normal organs. DLBAS has great potential to aid a key process in the radiation therapy workflow, helping optimise and reduce the clinical workload., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Importance: An increasing number of patients with breast cancer receiving neoadjuvant chemotherapy (NACT) undergo immediate breast reconstruction (IBR) with nipple-sparing mastectomy (NSM) or skin-sparing mastectomy (SSM) as surgical treatment. However, the oncologic efficacy and safety of this treatment sequencing strategy is unclear., Objective: To compare the long-term oncologic outcomes of IBR with NSM/SSM and conventional mastectomy (CM) alone for breast cancer in the NACT setting., Design, Setting, and Participants: A retrospective, propensity score-matched case-control study was conducted at Asan Medical Center, Seoul, Korea. A total of 1266 patients with breast cancer who underwent NACT followed by mastectomy with or without breast reconstruction between January 1, 2010, and November 30, 2016, were included. Data analysis was performed from July 1, 2019, to January 24, 2020. After propensity score matching, 323 patients who underwent IBR with NSM/SSM and 323 who underwent CM alone were selected for comparison of long-term oncologic outcomes., Main Outcomes and Measures: The 5-year local recurrence-free survival, disease-free survival, distant metastasis-free survival, and overall survival rates were calculated using the Kaplan-Meier method and compared using log-rank tests. Hazard ratios (HRs) and 95% CIs were estimated using the Cox proportional hazards regression model., Results: After matching, the median follow-up periods were 67 (range, 17-125) months for the IBR group and 68 (range, 17-126) months for the CM-alone group. Median age of the women in the IBR group was 42 (range, 23-72) years; median age of those in the CM-alone group was 46 (range, 30-75) years. No significant differences were observed between the IBR and CM-alone groups in local recurrence (3.7% vs 3.4%; P = .83), regional recurrence (7.1% vs 5.3%; P = .33), or distant metastasis (17.3% vs 18.6%; P = .68) rates. There was also no significant difference between the IBR and CM-alone groups in 5-year local recurrence-free survival (95.6% vs 96.7%; HR, 1.124; 95% CI, 0.495-2.549; P = .78), disease-free survival (76.5% vs 79.9%; HR, 1.089; 95% CI, 0.790-1.500; P = .60), distant metastasis-free survival (82.5% vs 82.5%; HR, 0.941; 95% CI, 0.654-1.355; P = .74), or overall survival (92.0% vs 89.3%; HR, 0.847; 95% CI, 0.530-1.353; P = .49) rates., Conclusions and Relevance: The long-term oncologic outcomes of IBR with NSM/SSM for breast cancer in this study appeared to be comparable to those of CM alone after NACT, suggesting the feasibility of IBR with NSM/SSM in the NACT setting.

Background/aims: We evaluated the efficacy of docetaxel and epirubicin as neoadjuvant chemotherapy in locally advanced breast cancer and assessed the predictive factors for response to neoadjuvant chemotherapy and prognostic factors related to relapse-free survival., Methods: Forty patients who received docetaxel and epirubicinas neoadjuvant chemotherapy for locally advanced breast cancer were evaluated retrospectively. Neoadjuvant chemotherapy consisted of intravenous injection of 75 mg/m2 docetaxel and 60 mg/m2 epirubucin on day 1, every 21 days, and two to six cycles., Results: Twenty-five (62.5%) patients showed a partial response, and 15 (37.5%) patients showed a stable disease in the first response evaluation after two or three cycles of neoadjuvant chemotherapy. In the second response evaluation of nine patients who received six cycles of neoadjuvant chemotherapy, one patient achieved a complete response, but two patients with hormone receptor-negative, human epidermal growth factor receptor 2-positive breast cancer experienced disease progression. Twenty-five (62.5%) patients experienced downstaging after neoadjuvant chemotherapy. Patients with > 20% pretreatment Ki-67 and decrease of Ki-67 between pre- and post-neoadjuvant chemotherapy showed a trend for better response. In multivariate analysis, advanced pathological stage showed a significant negative effect on relapse-free survival., Conclusion: Docetaxel and epirubicin neoadjuvant chemotherapy showed a good response in locally advanced breast cancer. Pretreatment Ki-67 and change of Ki-67 may play a role as predictive factor for response to neoadjuvant chemotherapy.

Background: Although nonalcoholic fatty liver disease (NAFLD) has been linked to breast cancer risk, the actual relationship remains unclear. Fatty liver index (FLI) is a noninvasive method for predicting NAFLD. We aimed to assess the association between FLI, a predictor of NAFLD, and breast cancer risk., Patients and Methods: Using the Korean National Health Insurance Corporation data, we reviewed 7,046,153 women who underwent biennial evaluations between 2009 and 2010. FLI was calculated using body mass index, waist circumference, triglyceride level, and gamma-glutamyl transferase level. FLI < 30 ruled out hepatic steatosis, while FLI ≥ 60 indicated NAFLD. Cox regression models were used for analysis., Results: Among the subjects, 51.8% (n = 3,606,079) were premenopausal women. In the premenopausal and postmenopausal groups, 32,145 (0.89%) and 28,103 (0.82%) women developed breast cancer, respectively (median follow-up, 7.02 years; interquartile range, 6.39-7.39 years). Mean FLI and standard deviation were lower in premenopausal women (11.24 ± 14.72 vs. 23.88 ± 19.54, P < .0001). Three groups were formed according to FLI: < 30 (n = 5,693,730, 80.81%), 30-60 (n = 1,031,025, 14.63%), and ≥ 60 (n = 321,398, 4.56%). FLIs of 30-60 and ≥ 60 were significantly associated with increased breast cancer risk in postmenopausal women (hazard ratio, 1.07; 95% confidence interval, 1.04-1.11; and hazard ratio, 1.11; 95% confidence interval, 1.05-1.17, respectively). No association was found in premenopausal women., Conclusion: High FLI, an indicator of NAFLD, could predict breast cancer in postmenopausal women., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Nipple-sparing mastectomy (NSM) has become increasingly prevalent for patients with ductal carcinoma in situ (DCIS) requiring mastectomy. However, few data regarding recurrence outcomes after NSM are available for this patient population. This study evaluated the locoregional recurrence (LRR) rate for patients with pure DCIS who underwent NSM followed by immediate breast reconstruction without adjuvant radiotherapy and investigated potential risk factors for LRR and/or nipple-areola complex recurrence (NR)., Methods: A retrospective chart review was performed for 199 consecutive patients with pure DCIS who underwent NSM and immediate breast reconstruction between March 2003 and December 2015. Risk factors for LRR and NR were analyzed using univariate (Chi square test) and multivariate (Cox model) methods., Results: The median follow-up duration after surgery was 97 months (range, 39-186 months). At 10 years, the LRR rate was 4.5%, and the NR rate was 3%. The univariate analysis showed that high nuclear grade, negative receptor status, positive human epidermal growth factor receptor 2 (HER2) status, and negative hormone receptor/positive HER2 subtype were associated with increased risk for NR. The multivariate analysis demonstrated that negative progesterone receptor status was an independent risk factor for LRR. However, margin status and tumor-to-nipple distance (TND) were not associated with increased risk for either LRR or NR., Conclusions: The study findings suggest that NSM can be a feasible surgical option even for DCIS with a TND of 1 cm or less if the retroareolar resection margin is negative for malignancy. Determining the molecular subtype of DCIS might be helpful in identifying patients at high risk for recurrence.

Activation of peroxisome proliferator-activated receptor γ (PPARγ) serves as a key factor in the proliferation and invasion of breast cancer cells and is a potential therapeutic target for breast cancer. However, the mechanisms underlying this effect remain largely unknown. Heme oxygenase-1 (HO-1) is induced and overexpressed in various cancers and is associated with features of tumor aggressiveness. Recent studies have shown that HO-1 is a major downstream target of PPARγ. In this study, we investigated the effects of induction of HO-1 by PPARγ on TPAinduced MMP-9 expression and cell invasion using MCF-7 breast cancer cells. TPA treatment increased NF-κB /AP-1 DNA binding as well as MMP-9 expression. These effects were significantly blocked by 15d-PGJ2, a natural PPARγ ligand. 15d-PGJ2 induced HO-1 expression in a dose-dependent manner. Interestingly, HO-1 siRNA significantly attenuated the inhibition of TPA-induced MMP-9 protein expression and cell invasion by 15d-PGJ2. These results suggest that 15d-PGJ2 inhibits TPA-induced MMP- 9 expression and invasion of MCF-7 cells by means of a heme oxygenase-1-dependent mechanism. Therefore, PPARγ/HO-1 signaling- pathway inhibition may be beneficial for prevention and treatment of breast cancer. [BMB Reports 2020; 53(4): 212-217].