Randomised controlled trials on radiation dose fractionation in breast cancer: systematic review and meta-analysis with emphasis on side effects and cosmesis.

OBJECTIVE: To provide a comprehensive assessment of various fractionation schemes in radiation therapy for breast cancer, with a focus on side effects, cosmesis, quality of life, risks of recurrence, and survival outcomes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (from inception to 23 October 2023). STUDY SELECTION: Included studies were randomised controlled trials focusing on conventional fractionation (CF; daily fractions of 1.8-2 Gy, reaching a total dose of 50-50.4 Gy over 5-6 weeks), moderate hypofractionation (MHF; fraction sizes of 2.65-3.3 Gy for 13-16 fractions over 3-5 weeks), and/or ultra-hypofractionation (UHF; schedule of only 5 fractions). DATA EXTRACTION: Two independent investigators screened studies and extracted data. Risk of bias and quality of evidence were assessed using the Cochrane Collaboration's tool and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach, respectively. DATA SYNTHESIS: Pooled risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. Heterogeneity was analysed using Cochran's Q test and I2 statistic. Network meta-analysis was used to integrate all available evidence. MAIN OUTCOME MEASURES: The pre-specified primary outcome was grade ≥2 acute radiation dermatitis and late radiation therapy related side effects; secondary outcomes included cosmesis, quality of life, recurrence, and survival metrics. RESULTS: From 1754 studies, 59 articles representing 35 trials (20 237 patients) were assessed; 21.6% of outcomes showed low risk of bias, whereas 78.4% had some concerns or high risk, particularly in outcome measurement (47.4%). The RR for grade ≥2 acute radiation dermatitis for MHF compared with CF was 0.54 (95% CI 0.49 to 0.61; P<0.001) and 0.68 (0.49 to 0.93; P=0.02) following breast conserving therapy and mastectomy, respectively. Hyperpigmentation and grade ≥2 breast shrinkage were less frequent after MHF than after CF, with RRs of 0.77 (0.62 to 0.95; P=0.02) and 0.92 (0.85 to 0.99; P=0.03), respectively, in the combined breast conserving therapy and mastectomy population. However, in the breast conserving therapy only trials, these differences in hyperpigmentation (RR 0.79, 0.60 to 1.03; P=0.08) and breast shrinkage (0.94, 0.83 to 1.07; P=0.35) were not statistically significant. The RR for grade ≥2 acute radiation dermatitis for UHF compared with MHF was 0.85 (0.47 to 1.55; P=0.60) for breast conserving therapy and mastectomy patients combined. MHF was associated with improved cosmesis and quality of life compared with CF, whereas data on UHF were less conclusive. Survival and recurrence outcomes were similar between UHF, MHF, and CF. CONCLUSIONS: MHF shows improved safety profile, cosmesis, and quality of life compared with CF while maintaining equivalent oncological outcomes. Fewer randomised controlled trials have compared UHF with other fractionation schedules, but its safety and oncological effectiveness seem to be similar with short term follow-up. Given the advantages of reduced treatment time, enhanced convenience for patients, and potential cost effectiveness, MHF and UHF should be considered as preferred options over CF in appropriate clinical settings, with further research needed to solidify these findings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023460249.

Utility of Clinical-Pathological Parameters for Exclusion of BRCA1/2 Mutation Carriers as Candidates for Partial Breast Irradiation.

PURPOSE: Several international groups have published guidelines to identify low-risk breast cancer (BC) patients who are eligible for partial breast irradiation (PBI). These include the American Society for Radiation Oncology (ASTRO), the European Society for Radiotherapy and Oncology (ESTRO), and ESTRO subgroups such as the Intraoperative radiation (IORT) Task Force and Groupe Européen de Curiethérapie (GEC) -ESTRO. Only ASTRO guidelines recommend against the use of PBI in known carriers of germline pathogenic variants (PVs) in BRCA1/2. The aim of this study was to evaluate the proportion of BC patients, subsequently found to be BRCA1/2 PV carriers who would be eligible for PBI based on clinical-pathologic criteria of the above-mentioned international guidelines. METHODS AND MATERIALS: Data were extracted from the medical records of consecutive BC BRCA1/2 PV carriers treated at a single institution between 2006 and 2023. Data included patient demographics, tumor characteristics, treatment, and disease outcomes. RESULTS: Overall, 498 patients with 518 primary tumors were analyzed. Of these, 282 (12 of them with synchronous bilateral disease) presented with unknown genetic status at diagnosis and formed the study cohort. The median age at diagnosis was 42.7 years (range, 23.8-77.9). Based on the recent ASTRO guidelines (not including conditionally recommended criteria), 17 of 294 (5.8%) of the carriers had tumors that would be eligible for PBI, including 3 Her2-positive tumors and 5 patients diagnosed between ages 40 and 49 years. Using the ESTRO IORT and the ACROP-ESTRO PBI criteria, 9 of 294 (3%) would be eligible, whereas with the GEC-ESTRO low-risk criteria, 31 of 294 (10.5%) of the carriers would be eligible, and their intermediate risk criteria would increase eligibility for PBI by an additional 8.2% (overall 18.7%). CONCLUSIONS: Using clinical-pathologic criteria published in international guidelines, 3% to 18% of BRCA1/2 PV carriers will have tumors eligible for PBI. Therefore, especially in populations who are at high risk for being BRCA1/2 PV carriers, we recommend adhering to stricter guidelines. In our cohort, ASTRO, ESTRO-IORT, and ESTRO PBI had the lowest probability of identifying BRCA1/2 PV carriers as eligible for PBI.

Residual breast tissue after mastectomy and reconstruction: A substudy of the Spatial location of breast cancer local rECurRence aftEr masTectomy (SECRET) project.

The current project is part of the Spatial location of breast cancer local rECurRence aftEr masTectomy (SECRET) study (NCT06130111). Herein we compared the chest wall thickness after non-skin sparing mastectomy (non-SSM) with the chest wall thickness after SSM, as a surrogate for residual breast tissue after mastectomy. METHODS: The study was approved by the ethics committee of relevant institutions. Data of patients with a local recurrence (LR) after non-SSM was collected from the Netherlands Cancer Registry (NCR); data of patients undergoing SSM were collected from Sheba Medical Center. Student's t-test was used to evaluate the difference between the cohorts. Chest wall thickness was measured on postoperative images. RESULTS: Out of 4949 patients who underwent mastectomy from the NCR cohort, a total of 173 (3.5 %) had a LR at 5 years, of these a total of 153 patients included in the non-SSM cohort. The median age was 59 years (age 33-92), LR occurred at a median of 23.6 months (2.5-60 months). The SSM cohort included 84 patients, with a median age of 38.4 years (28-63.5), overall, 5 LRs occurred at a median of 15 months (5-46 months). The SSM cohort had significantly thicker chest walls compared to non-SSM (p < 0.001). Most LRs in both groups occurred in the subcutis. CONCLUSION: The chest wall thickness differed according to mastectomy procedures. Most of the LR occurred at the subcutis. The role of residual breast tissue and residual cancer in relation to type of mastectomy should be further investigated.

A BRILLIANT-BRCA study: residual breast tissue after mastectomy and reconstruction.

INTRODUCTION: Different types of mastectomies leave different amounts of residual breast tissue. The significance of the residual breast volume (RBV) is not clear. Therefore, we developed an MRI tool that allows to easily assess the RBV. In this study we evaluated factors associated with RBV after skin or nipple sparing mastectomy (SSM/NSM) in breast cancer BRCA pathogenic variant (PV) carriers who underwent both therapeutic and risk reducing SSM/NSM and its relation to breast cancer outcomes using an innovative MRI-based tool. METHODS: Data of breast cancer BRCA PV who were treated between 2006 and 2020 were retrieved from of the oncogenetics unit databases. Only patients who underwent SSM/NSM and had a postoperative breast MRI available for analysis were included. Data collected included demographics, clinicopathological features, and outcomes. The MRI tool was developed by a breast cancer imaging laboratory. A logistic regression test and 95% confidence interval (CI) were used to assess the associated risk of increased RBV. A forward stepwise linear regression was used to correlate tumour-patient specific factors and RBV, and a Kaplan-Meier curve to show the probability of locoregional relapse. RESULTS: A total of 84 patients undergoing 89 mastectomies were included. At a median follow-up of 98 months, 5 local, 2 regional, and 4 distant recurrences were observed. RBV was not significantly related with breast cancer outcomes (p value = NS). A higher body mass index (BMI) was associated with a higher RBV (p < 0.0001). A larger number of involved axillary nodes was associated with a smaller RBV (p = 0.025). The RBV on the risk-reducing mastectomy side was significantly higher compared to the breast cancer side (p value = 0.007). Local recurrences occurred in the vicinity of the primary tumour.

EBCC-14 manifesto: Addressing disparities in access to innovation for patients with metastatic breast cancer across Europe.

The European Breast Cancer Council (EBCC) traditionally identifies controversies or major deficiencies in the management of patients with breast cancer and selects a multidisciplinary expert team to collaborate in setting crucial principles and recommendations to improve breast cancer care. The 2024 EBCC manifesto focuses on disparities in the care of patients with metastatic breast cancer. There are several reasons for existing disparities both between and within countries. Our recommendations aim to address the stigma of metastatic disease, which has led to significant disparities in access to innovative care regardless of the gross national income of a country. These recommendations are for different stakeholders to promote the care of patients with metastatic breast cancer across Europe and worldwide.

Pathology and resection margins following mastectomy prior to immediate breast reconstruction.

Risk of local recurrence (LR) (and even distant disease-free survival) after mastectomy is associated with margin status. Furthermore, the vast majority of LR are located at the anterior (superficial) margin. Margins in mastectomy are considered anatomical borders and not true resection margins; such a conception may erroneously lead to underestimation of the risk of LR after mastectomy. If dissection is accurate along the fascia, only skin, subcutaneous tissue and minimal residual breast gland tissue (rBGT) are expected to remain in the patient. However, the subcutaneous fascia is an inconsistent anatomical structure that may be absent in almost half of patients. Studies and routine clinical practice suggest that resection may frequently, though often focally, be within the breast glandular tissue leaving various amounts of rBGT. Such areas may be nidus for subsequent de novo or recurrent premalignant or malignant disease. There is no consensus on handling of close/positive margins and intervention is extrapolated from studies on breast conserving surgery with subsequent radiotherapy. Handling of a close/positive margin is complicated by poor correlation between the ex vivo findings on the specimen and the attempt to relocate the area of concern in a patient with reconstructed breasts. In this clinical practice review, we strongly advocate for reporting of the lesion-to-margin distance in mastectomies to collect further evidence on the association between LR and margin status.

International multidisciplinary consensus on the integration of radiotherapy with new systemic treatments for breast cancer: European Society for Radiotherapy and Oncology (ESTRO)-endorsed recommendations.

Novel systemic therapies for breast cancer are being rapidly implemented into clinical practice. These drugs often have different mechanisms of action and side-effect profiles compared with traditional chemotherapy. Underpinning practice-changing clinical trials focused on the systemic therapies under investigation, thus there are sparse data available on radiotherapy. Integration of these new systemic therapies with radiotherapy is therefore challenging. Given this rapid, transformative change in breast cancer multimodal management, the multidisciplinary community must unite to ensure optimal, safe, and equitable treatment for all patients. The aim of this collaborative group of radiation, clinical, and medical oncologists, basic and translational scientists, and patient advocates was to: scope, synthesise, and summarise the literature on integrating novel drugs with radiotherapy for breast cancer; produce consensus statements on drug-radiotherapy integration, where specific evidence is lacking; and make best-practice recommendations for recording of radiotherapy data and quality assurance for subsequent studies testing novel drugs.

Incidental Axillary Lymphadenopathy Found on Radiation Planning Computed Tomography.

PURPOSE: The aim of this study was to evaluate the rate of axillary node-positive disease in patients with early breast cancer who had a suspicious axillary lymph node on radiation planning computed tomography (CT). METHODS AND MATERIALS: A retrospective review was conducted of the medical records of all patients with breast cancer who were referred for axillary ultrasound from the radiation unit to the breast imaging unit at the Meirav Breast Center, Sheba Medical Center, from 2012 to 2022. Ethics approval was obtained. Only the records of patients who were referred due to an abnormal axillary lymph node seen on radiation planning CT were further evaluated. RESULTS: During the study period, a total of 21 patients were referred to the breast imaging unit for evaluation of suspicious nodes seen on radiation planning CT. Of these, 3 cases were excluded. A total of 15 out of the 18 (83%) patients included had an abnormal lymph node in the ultrasound, and an ultrasound-guided biopsy was recommended (BI-RADS 4). Of these, 3 (out of 15, 20%) had a positive biopsy for tumor cells from the axillary lymph node. Two were cases after primary systemic therapy without complete pathologic response. Thickening of the lymph node cortex and complete loss of the central fatty hilum were associated with pathologic lymph node. CONCLUSION: Sonar had limited ability to differentiate reactive nodes from involved nodes. The presence of lymph nodes with loss of cortical-hilum differentiation on ultrasound together with clinical features are parameters that can help guide the need of further biopsy. Histopathology evaluation is important to make the diagnosis of residual axillary disease. Future studies and guidelines are needed to improve the diagnostic abilities and reduce the number of patients who are undergoing biopsy for noninvolved nodes.

Omission of radiation therapy after breast-conserving surgery for biologically favourable tumours in younger patients: The wrong answer to the right question.

In this perspective paper, the findings of the recently published LUMINA study are critically evaluated, with an emphasis on the need for careful interpretation and a thoughtful approach in clinical practice. The LUMINA trial, which investigates the role of adjuvant endocrine therapy in low-risk breast cancer patients, is assessed for its limitations, including a highly selective patient cohort and an insufficient follow-up period. The importance of long-term data and further trials to inform clinical decisions effectively is emphasized. While the LUMINA study does not support an immediate change in practice, it is seen as a foundation for generating hypotheses to guide ongoing clinical trials. This important study has served as inspiration to develop this perspective paper, which takes into account ongoing studies and the toxicity profile of postoperative treatments in low-risk recurrence breast cancer. The need for a patient-cantered approach is stressed, considering individual wishes and desires in decision-making, despite the complexity of articulating these aspects in guidelines. A wise interpretation of available findings is essential to ensure sound clinical decision-making before broadly applying omission of radiation therapy.

Optimising of axillary therapy in breast cancer: lessons from the past to plan for a better future.

In this narrative review, we aim to explore the ability of radiation therapy to eradicate breast cancer regional node metastasis. It is a journey through data of older trials without systemic therapy showing the magnitude of axillary therapy (surgery versus radiation) on cancer control. Considering that both systemic and loco-regional therapies were shown to reduce any recurrence with a complex interaction, our review includes surgical, radiation, and radiobiology consideration for breast cancer, and provide our view of future practise. The aim is to provide information optimise radiation therapy in the era of primary systemic therapy.

Essential requirements for reporting radiation therapy in breast cancer clinical trials: An international multi-disciplinary consensus endorsed by the European Society for Radiotherapy and Oncology (ESTRO).

The European Society for Radiotherapy and Oncology (ESTRO) has advocated the establishment of guidelines to optimise precision radiotherapy (RT) in conjunction with contemporary therapeutics for cancer care. Quality assurance in RT (QART) plays a pivotal role in influencing treatment outcomes. Clinical trials incorporating QART protocols have demonstrated improved survival rates with minimal associated toxicity. Nonetheless, in routine clinical practice, there can be variability in the indications for RT, dosage, fractionation, and treatment planning, leading to uncertainty. In pivotal trials reporting outcomes of systemic therapy for breast cancer, there is limited information available regarding RT, and the potential interaction between modern systemic therapy and RT remains largely uncharted. This article is grounded in a consensus recommendation endorsed by ESTRO, formulated by international breast cancer experts. The consensus was reached through a modified Delphi process and was presented at an international meeting convened in Florence, Italy, in June 2023. These recommendations are regarded as both optimal and essential standards, with the latter aiming to define the minimum requirements. A template for a case report form (CRF) has been devised, which can be utilised by all clinical breast cancer trials involving RT. Optimal requirements include adherence to predefined RT planning protocols and centralised QART. Essential requirements aim to reduce variations and deviations from the guidelines in RT, even when RT is not the primary focus of the trial. These recommendations underscore the significance of implementing these practices in both clinical trials and daily clinical routines to generate high-quality data.

The King is in the altogether: Radiation therapy after oncoplastic breast surgery.

Breast cancer is the most common malignancy, and the majority of the patients are diagnosed at an early disease stage. Breast conservation is the preferred locoregional approach, and oncoplastic breast conservation surgery is becoming more popular. This narrative review aims to discuss the challenges and uncertainties in target volume definition for postoperative radiation after these procedures, to improve radiation therapy decisions and encourage multidisciplinary.

Re-irradiation in clinical practice: Results of an international patterns of care survey within the framework of the ESTRO-EORTC E2-RADIatE platform.

BACKGROUND: Re-irradiation is an increasingly utilized treatment for recurrent, metastatic or new malignancies after previous radiotherapy. It is unclear how re-irradiation is applied in clinical practice. We aimed to investigate the patterns of care of re-irradiation internationally. MATERIAL/METHODS: A cross-sectional survey conducted between March and September 2022. The survey was structured into six sections, each corresponding to a specific anatomical region. Participants were instructed to complete the sections of their clinical expertise. A total of 15 multiple-choice questions were included in each section, addressing various aspects of the re-irradiation process. The online survey targeted radiation and clinical oncologists and was endorsed by the European Society for Radiotherapy and Oncology (ESTRO) and the European Organisation for Research and Treatment of Cancer (EORTC). RESULTS: 371 physicians from 55 countries across six continents participated. Participants had a median professional experience of 16 years, and the majority (60%) were affiliated with an academic hospital. The brain region was the most common site for re-irradiation (77%), followed by the pelvis (65%) and head and neck (63%). Prolonging local control was the most common goal (90-96% across anatomical regions). The most common minimum interval between previous radiotherapy and re-irradiation was 6-12 months (45-55%). Persistent grade 3 or greater radiation-induced toxicity (77-80%) was the leading contraindication. Variability in organs at risk dose constraints for re-irradiation was observed. Advanced imaging modalities and conformal radiotherapy techniques were predominantly used. A scarcity of institutional guidelines for re-irradiation was reported (16-19%). Participants from European centers more frequently applied thoracic and abdominal re-irradiation. Indications did not differ between academic and non-academic hospitals. CONCLUSION: This study highlights the heterogeneity in re-irradiation practices across anatomical regions and emphasizes the need for high-quality evidence from prospective studies to guide treatment decisions and derive safe cumulative dose constraints.

Evaluating the ability of an artificial-intelligence cloud-based platform designed to provide information prior to locoregional therapy for breast cancer in improving patient's satisfaction with therapy: The CINDERELLA trial.

BACKGROUND: Breast cancer therapy improved significantly, allowing for different surgical approaches for the same disease stage, therefore offering patients different aesthetic outcomes with similar locoregional control. The purpose of the CINDERELLA trial is to evaluate an artificial-intelligence (AI) cloud-based platform (CINDERELLA platform) vs the standard approach for patient education prior to therapy. METHODS: A prospective randomized international multicentre trial comparing two methods for patient education prior to therapy. After institutional ethics approval and a written informed consent, patients planned for locoregional treatment will be randomized to the intervention (CINDERELLA platform) or controls. The patients in the intervention arm will use the newly designed web-application (CINDERELLA platform, CINDERELLA APProach) to access the information related to surgery and/or radiotherapy. Using an AI system, the platform will provide the patient with a picture of her own aesthetic outcome resulting from the surgical procedure she chooses, and an objective evaluation of this aesthetic outcome (e.g., good/fair). The control group will have access to the standard approach. The primary objectives of the trial will be i) to examine the differences between the treatment arms with regards to patients' pre-treatment expectations and the final aesthetic outcomes and ii) in the experimental arm only, the agreement of the pre-treatment AI-evaluation (output) and patient's post-therapy self-evaluation. DISCUSSION: The project aims to develop an easy-to-use cost-effective AI-powered tool that improves shared decision-making processes. We assume that the CINDERELLA APProach will lead to higher satisfaction, better psychosocial status, and wellbeing of breast cancer patients, and reduce the need for additional surgeries to improve aesthetic outcome.

Designing clinical trials based on modern imaging and metastasis-directed treatments in patients with oligometastatic breast cancer: a consensus recommendation from the EORTC Imaging and Breast Cancer Groups.

Breast cancer remains the most common cause of cancer death among women. Despite its considerable histological and molecular heterogeneity, those characteristics are not distinguished in most definitions of oligometastatic disease and clinical trials of oligometastatic breast cancer. After an exhaustive review of the literature covering all aspects of oligometastatic breast cancer, 35 experts from the European Organisation for Research and Treatment of Cancer Imaging and Breast Cancer Groups elaborated a Delphi questionnaire aimed at offering consensus recommendations, including oligometastatic breast cancer definition, optimal diagnostic pathways, and clinical trials required to evaluate the effect of diagnostic imaging strategies and metastasis-directed therapies. The main recommendations are the introduction of modern imaging methods in metastatic screening for an earlier diagnosis of oligometastatic breast cancer and the development of prospective trials also considering the histological and molecular complexity of breast cancer. Strategies for the randomisation of imaging methods and therapeutic approaches in different subsets of patients are also addressed.

The Lucerne Toolbox 2 to optimise axillary management for early breast cancer: a multidisciplinary expert consensus.

Clinical axillary lymph node management in early breast cancer has evolved from being merely an aspect of surgical management and now includes the entire multidisciplinary team. The second edition of the "Lucerne Toolbox", a multidisciplinary consortium of European cancer societies and patient representatives, addresses the challenges of clinical axillary lymph node management, from diagnosis to local therapy of the axilla. Five working packages were developed, following the patients' journey and addressing specific clinical scenarios. Panellists voted on 72 statements, reaching consensus (agreement of 75% or more) in 52.8%, majority (51%-74% agreement) in 43.1%, and no decision in 4.2%. Based on the votes, targeted imaging and standardized pathology of lymph nodes should be a prerequisite to planning local and systemic therapy, axillary lymph node dissection can be replaced by sentinel lymph node biopsy ( ± targeted approaches) in a majority of scenarios; and positive patient outcomes should be driven by both low recurrence risks and low rates of lymphoedema.

Looking Back: International Practice Patterns in Breast Radiation Oncology From a Case-Based Survey Across 54 Countries During the First Surge of the COVID-19 Pandemic.

PURPOSE: The COVID-19 pandemic has profoundly affected cancer care worldwide, including radiation therapy (RT) for breast cancer (BC), because of risk-based resource allocation. We report the evolution of international breast RT practices during the beginning of the pandemic, focusing on differences in treatment recommendations between countries. MATERIALS AND METHODS: Between July and November 2020, a 58-question survey was distributed to radiation oncologists (ROs) through international professional societies. Changes in RT decision making during the first surge of the pandemic were evaluated across six hypothetical scenarios, including the management of ductal carcinoma in situ (DCIS), early-stage, locally advanced, and metastatic BC. The significance of changes in responses before and during the pandemic was examined using chi-square and McNemar-Bowker tests. RESULTS: One thousand one hundred three ROs from 54 countries completed the survey. Incomplete responses (254) were excluded from the analysis. Most respondents were from the United States (285), Japan (117), Italy (63), Canada (58), and Brazil (56). Twenty-one percent (230) of respondents reported treating at least one patient with BC who was COVID-19-positive. Approximately 60% of respondents reported no change in treatment recommendation during the pandemic, except for patients with metastatic disease, for which 57.7% (636/1,103; P < .0005) changed their palliative practice. Among respondents who noted a change in their recommendation during the first surge of the pandemic, omitting, delaying, and adopting short-course RT were the most frequent changes, with most transitioning to moderate hypofractionation for DCIS and early-stage BC. CONCLUSION: Early in the COVID-19 pandemic, significant changes in global RT practice patterns for BC were introduced. The impact of published results from the FAST FORWARD trial supporting ultrahypofractionation likely confounded the interpretation of the pandemic's independent influence on RT delivery.

Safety profile of trastuzumab-emtansine (T-DM1) with concurrent radiation therapy: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: In recent years, the treatment landscape for breast cancer has undergone significant advancements, with the introduction of several new anticancer agents. One such agent is trastuzumab emtansine (T-DM1), an antibody drug conjugate that has shown improved outcomes in both early and advanced breast cancer. However, there is currently a lack of comprehensive evidence regarding the safety profile of combining T-DM1 with radiation therapy (RT). In this study, we aim to provide a summary of the available data on the safety of combining RT with T-DM1 in both early and metastatic breast cancer settings. MATERIALS AND METHODS: This systematic review and meta-analysis project is part of the consensus recommendations by the European Society for Radiotherapy and Oncology (ESTRO) Guidelines Committee on integrating RT with targeted treatments for breast cancer. A thorough literature search was conducted using the PUBMED/MedLine, Embase, and Cochrane databases to identify original studies focusing on the safety profile of combining T-DM1 with RT. RESULTS: After applying eligibility criteria, nine articles were included in the meta-analysis. Pooled data from these studies revealed a high incidence of grade 3 + radionecrosis (17%), while the rates of grade 3 + radiation-related pneumonitis (<1%) and skin toxicity (1%) were found to be very low. CONCLUSION: Although there is some concern regarding a slight increase in pneumonitis when combining T-DM1 with postoperative RT, the safety profile of this combination was deemed acceptable for locoregional treatment in non-metastatic breast cancer. However, caution is advised when irradiating intracranial sites concurrently with T-DM1. There is a pressing need for international consensus guidelines regarding the safety considerations of combining T-DM1 and RT for breast cancer.