Youlia M. Kirova

La radiothérapie externe à ultra-haut débit de dose (UHDR-RT), exploitant l’effet FLASH et communément appelée radiothérapie FLASH, représente une modalité émergente susceptible d’améliorer l’index thérapeutique par rapport à la radiothérapie conventionnelle (CONV-RT). Cette technique délivre des rayonnements ionisants à des débits de dose extrêmement élevés, de l’ordre de plusieurs dizaines de Gy/s, contrairement aux protocoles cliniques conventionnels qui délivrent généralement quelques Gy par minute. Les données précliniques indiquent que l’administration de rayonnements à de tels débits ultra-élevés sur des temps d’exposition très courts peut réduire significativement la toxicité vis-à-vis des tissus sains tout en maintenant un contrôle tumoral équivalent, un phénomène appelé effet FLASH. Cet effet a été démontré avec des faisceaux d’électrons, de photons et de protons. Malgré son potentiel prometteur, plusieurs questions essentielles restent en suspens, notamment en ce qui concerne les paramètres de prescription du traitement, tels que le fractionnement des doses, la dose totale administrée et les réponses biologiques sous-jacentes. De plus, les mécanismes radiobiologiques à l’origine de l’effet FLASH ne sont pas encore complètement élucidés. À l’heure actuelle, aucune recommandation internationale ne standardise l’assurance qualité des machines et des patients, ni la planification des traitements en vue d’une application clinique. Néanmoins, les progrès vers l’intégration clinique de la radiothérapie FLASH se poursuivent, avec des efforts visant à surmonter ces défis techniques et biologiques et à étendre ses applications potentielles.

Local recurrence after primary breast cancer treatment remains a complex clinical scenario in patients previously treated with breast‐conserving therapy and radiotherapy. For decades, salvage mastectomy was considered the standard treatment for ipsilateral breast tumor recurrence, largely because of concerns about local control after repeat lumpectomy and cumulative toxicity after reirradiation. This paradigm has progressively changed. Retrospective comparative series, prospective Phase II data, large multicenter brachytherapy cohorts, and population‐based analyses suggest that second breast‐conserving treatment combined with reirradiation can achieve favorable local control and survival in carefully selected patients, without an apparent survival impact compared with mastectomy. The strongest evidence supports partial breast reirradiation after complete resection of small, unifocal recurrences occurring after a sufficient interval from prior radiotherapy. External beam radiotherapy, multicatheter brachytherapy, and intraoperative radiotherapy each offer distinct technical advantages, toxicity profiles, and levels of evidence. Across modalities, outcomes are most favorable in patients with limited disease, complete resection, long interval from initial treatment, and favorable tumor biology, whereas early recurrence, gross residual disease, skin or chest wall involvement, and adverse molecular subtype are associated with poorer outcomes. Risk stratification tools, including the GEC‐ESTRO APBI classification and TAM score, may help refine patient selection, but practice remains heterogeneous and cumulative dose constraints are not standardized. Future studies should define optimal reirradiation techniques, normal tissue constraints, integration with modern systemic therapies, and patient‐reported outcomes. Second breast‐conserving treatment should therefore be viewed as a personalized alternative to salvage mastectomy in selected patients, rather than as a universal replacement.

The integration of modern systemic therapies with radiotherapy (RT) represents a promising strategy in breast cancer management, enhancing both locoregional control and systemic disease outcomes. This expert consensus from the Institut Curie Breast Radiotherapy Group focuses exclusively on modern systemic agents, synthesizing current evidence on the concurrent administration of human epidermal growth factor receptor 2‐targeted agents (trastuzumab, pertuzumab, trastuzumab emtansine, trastuzumab deruxtecan), cyclin‐dependent kinase 4 and 6 inhibitors (palbociclib, ribociclib), immunotherapies (pembrolizumab), poly(ADP‐ribose) polymerase inhibitors (olaparib), and new antibody‐drug conjugates (sacituzumab govitecan). Drawing from extensive clinical experience, including retrospective and prospective studies conducted at Institut Curie, this review provides a comprehensive analysis of the feasibility and safety of these novel combinations, ensuring an evidence‐based approach to optimizing breast cancer treatment strategies. In addition to systemic therapy considerations, this review highlights the importance of advanced RT techniques, including proton therapy, isocentric lateral decubitus positioning, and volumetric modulated arc therapy with deep inspiration breath hold, which play a crucial role in minimizing cardiac and pulmonary toxicities, particularly in patients receiving cardiotoxic agents or those with predisposing risk factors. By integrating both systemic advancements and optimized radiation delivery, this review provides a practical framework for the safe and effective combination of modern breast cancer therapies.

Background/Objectives: Male breast cancer (MBC) is a rare malignancy representing less than 1% of all breast cancer cases, with rising incidence worldwide. Current treatment strategies largely rely on extrapolation from female breast cancer, despite clear biological and clinical distinctions. This review aims to summarize current knowledge on non-metastatic MBC, with a particular focus on genetic predisposition, tumor biology, and recent therapeutic advances. Methods: A systematic literature search was conducted using PubMed and PMC databases to identify clinical trials, observational studies and systematic reviews related to MBC published up to 1st June, 2025. Studies were selected for their relevance to genetic and molecular features, as well as treatment outcomes in non-metastatic disease. Results: Fifty-one studies were included in the review. Findings confirm the predominance of hormone receptor–positive tumors in MBC and underscore the central role of BRCA2 mutations. Germline mutations in BRCA2 and BRCA1 were reported in approximately 1 and 2% of male cases, respectively. Additional germline alterations were identified in PALB2, CHEK2, and other DNA repair genes. Comparative analyses of surgical approaches showed no significant difference in survival between breast-conserving surgery and mastectomy. Postmastectomy radiotherapy improved overall survival compared to surgery alone. Adjuvant tamoxifen therapy was independently associated with significant survival benefits, although adherence remains a challenge. Conclusions: MBC is a biologically distinct and molecularly heterogeneous disease. Breast-conserving surgery appears safe and effective in selected patients. Adjuvant radiotherapy and tamoxifen confer clear survival advantages. The lack of male-specific clinical trials remains a major limitation in optimizing evidence-based care for MBC.

The combination in patients with HER2-positive and HER2-low metastatic breast cancer (MBC) of Concurrent Trastuzumab Deruxtecan (T-DXd) and Radiation Therapy (RT) is not enough studied. We conducted a retrospective study including patients treated between 11/2020 and 01/2024. Patients with HER2-positive and HER2-low MBC who received concurrent T-DXd and RT were identified. Data on patient demographics, treatment regimens, radiation doses, toxicity profiles, efficacy, and treatment discontinuations were collected. The toxicities were graded using CTCAE V5.0. Population of 33 patients with HER2-positive and HER2-low MBC who underwent concurrent T-DXd&RT, were studied. The median follow-up (FU) was 14 months. There were 39.4 partial remissions and 9.4 attained complete remission. In addition, 39.4% experienced stable disease, and 12.1% faced disease progression necessitating a change in therapy. Safety assessment revealed that acute toxicities were mainly associated with systemic treatment. Survival analysis showed 11 deaths (33.3%) during the FU period, with a median overall survival of 26 months and median progression-free survival of 12 months. The combination of T-DXd with RT in demonstrates promising efficacy with a manageable safety profile. Further studies are warranted to fully elucidate the potential synergistic effects of this treatment regimen and its impact on patient outcome.

Background: Atrial fibrillation (AF) after radiotherapy (RT) in patients with breast cancer (BC) is a relatively new and understudied topic. AF can increase the risk of stroke and other serious cardiovascular complications, compromising patients’ quality of life and survival. Screening of AF, both asymptomatic and symptomatic forms, is therefore essential for optimal management. Objective: The aim of the Watch Your Heart After Radiotherapy for Breast Cancer (WATCH) study is to assess the incidence of AF (symptomatic or asymptomatic) occurring throughout a 5-year follow-up after RT and to investigate whether cardiac radiation exposure is associated with the occurrence of such events. Methods: WATCH is a cohort study that will include 200 patients over 65 years old, treated with RT for BC 5 years before inclusion and without a history of AF. Cross-sectional screening for AF at the time of the scheduled 5-year post-RT visit will be conducted by recording data from a Withings ScanWatch smartwatch for 1 month, confirmed by an electrocardiogram (ECG), and validated by a physician. In addition, a transthoracic echocardiography (TTE) will be performed, providing a comprehensive assessment of cardiac structures, and allowing us to investigate the underlying etiology and assess the risk of complications. Patients’ medical records will provide retrospective information about the timing and risk factors for the occurrence of AF and other arrhythmias and cardiac diseases during the 5 years following RT. The development of deep learning algorithms for autosegmentation analysis of potentially critical substructures for the occurrence of AF, including cardiac chambers, the sinoatrial node, the atrioventricular node, coronary arteries, and pulmonary veins (PVs), will produce dosimetry linked to previous RT treatment for all contoured structures. Results: Enrollment started in October 2023 and will continue until mid-2026 to include 200 patients, which will ensure an 80% statistical power to detect a significant difference in AF incidence around 15% for the group of patients moderately exposed (75th percentile of the mean heart radiation dose). The results are expected by the end of 2026. Conclusions: This study will contribute to generating new knowledge on AF after RT for BC and help considering the inclusion of AF screening into routine clinical practice for these patients. Identifying the dose-risk associations would improve RT delivery protocols to limit the occurrence of different forms of AF and, if necessary, initiate appropriate treatment. Trial Registration: ClinicalTrials.gov NCT06073509; clinicaltrials.gov/study/NCT06073509?id=NCT06073509&rank=1. International Registered Report Identifier (IRRID): DERR1-10.2196/67875

Objective: The immune system has been recognized as an organ-at-risk in oesophageal and lung cancers. The potential impact of deep inspiration breath-hold (DIBH) and fractionation on immune system preservation in breast radiation therapy is presently unknown. The aim of this study was to assess the magnitude of the benefit of DIBH and hypofractionation on immune system exposure in adjuvant irradiation of right breast cancers. Methods: Ten consecutive patients treated volumetric-modulated arc therapy (VMAT) with DIBH for adjuvant locoregional irradiation of the right breast where included. The effective dose to the immune system (EDIC) was calculated for each patient (the absolute contribution of the lungs, heart, liver and total integral dose to the EDIC was evaluated) based on normo-fractionated and hypofractionated regimens, with or without DIBH. Results: EDIC was significantly lower in DIBH than in free breathing, both in standard fractionation (2.81 Gy [range: 2.44; 3.38] vs 3.1 Gy [2.63; 3.94], P < . 01) and hypofractionation (2.15 Gy [1.87; 2.58] vs 2.35 Gy [2.02; 2.96], P < .01), corresponding to a relative EDIC reduction of approximately 10% with DIBH. EDIC was lower with hypofractionation with free breathing than with conventional fractionation with DIBH (P < .01). Conclusion: DIBH significantly reduces the dose to the immune system by 10% in cases of locoregional irradiation of right breast cancers, and moderate hypofractionation results in an EDIC gain compared with any standard fractionation treatment. Pending formal demonstration of a relationship between dose to the immune system and survival, as is the case in other localizations, we suggest as a precaution the use of DIBH combined with hypofractionated treatment in cases where immune sparing seems most important, such as breast cancers with a poor response after preoperative immunotherapy. Advances in knowledge: DIBH significantly reduces the dose to the immune system by 10% in cases of locoregional irradiation of right breast cancers, and moderate hypofractionation results in an EDIC gain compared with any standard fractionation treatment. Pending formal demonstration of a relationship between dose to the immune system and survival, as is the case in other localizations, we suggest as a precaution the use of DIBH combined with hypofractionated treatment in cases where immune sparing seems most important, such as breast cancers with a poor response after preoperative immunotherapy.