Tumour-infiltrating lymphocytes (TILs) are prognostic and predictive biomarkers in breast cancer. High pre-treatment TILs are associated with a favourable prognosis and improved response to systemic therapies. However, the role of TILs in mediating response to radiotherapy in breast cancer remains underexplored, with scarce clinical evidence to date. In this Review, we present an overview of current evidence and potential mechanisms, highlight opportunities for integrating TILs into radiation oncology trials and clinical practice, and call for standardised TIL reporting to accelerate biomarker-driven individualisation of radiotherapy in breast cancer.

Background/Objectives: We performed a systematic review of the current clinical and preclinical literature on the use of particle therapy, DDRi, and/or immunotherapy, specifically for pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, carbon) either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICI), or X-ray radiotherapy (XRT) in combination with DDRi/ICI. Results: In total, 133 studies met the inclusion criteria, including 62 clinical studies. Clinically, particle therapies show excellent local control and normal tissue sparing, with manageable toxicity profiles. Trials with any form of radiation and DDRi are few, potentially owing to toxicity concerns. ICI combinations showed promising efficacy with XRT, with no randomized trials comparing them to particle radiation. Conclusions: Particle radiation and/or DDRi have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increase response rates to immunotherapy (presented in the companion manuscript). Despite strong preclinical evidence and rationale, clinical trials including all three modalities are scarce. Existing evidence suggests a potential benefit based on extrapolation from photon-based studies and supports prospective evaluation with careful attention to treatment-related toxicity, which remains a concern.

PURPOSE:We sought to compare target coverage, skin dose, physician-assessed adverse events, and patient-reported skin outcomes in a large cohort of patients receiving postmastectomy intensity modulated proton therapy (IMPT) or photon radiation therapy (XRT). METHODS AND MATERIALS:Women with unilateral, noninflammatory breast cancer treated with postmastectomy radiation therapy using IMPT or XRT to 50 Gy relative biological effectiveness (RBE) were included. Skin planning objectives for both modalities prioritized ≥90% of the skin volume receiving >90% of the prescription dose, which is expected to control microscopic disease, while maintaining dose homogeneity. IMPT planning objectives limited the dose to 1 cc of skin to ≤105% of the prescription dose, with an ideal constraint of ≤96%. Target and skin dosimetry were evaluated. Acute Common Toxicity Criteria for Adverse Events (CTCAE) grade ≥2 dermatitis and skin-specific patient-reported outcomes using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) were compared between modalities. RESULTS:Among 176 women (93 IMPT, 83 XRT), the median skin D0.01cc, D1cc, and D10cc were higher in XRT plans than in IMPT plans, although the differences were all less than 3%. Acute grade ≥2 dermatitis occurred in 47% (IMPT) and 48% (XRT) and was not associated with treatment modality (P = .91). Grade 3 dermatitis occurred in 3% (IMPT) and 7% (XRT) (P = .22), with no grade 4 events. At 12 months post-RT, XRT patients reported more skin color changes than IMPT patients (26% vs 6%, P = .04), the only significantly different patient-reported skin outcome. CONCLUSIONS:Patient and provider-reported adverse skin events were mild and comparable between IMPT and XRT. These findings highlight the importance of skin constraints for IMPT planning to titrate an optimal skin dose.

Introduction Antibody–drug conjugates (ADCs) are now widely used in breast cancer across multiple disease subtypes. With increasing clinical use, treatment-related toxicities have become an important factor in therapeutic decision-making. However, comparative safety data among ADCs are limited because direct head-to-head trials are lacking. Methods We conducted a systematic review and Bayesian network meta-analysis of randomized controlled trials evaluating ADCs in breast cancer, with the literature search updated through March 31, 2025. Treatment-related adverse events (TRAEs) and serious adverse events (SAEs) were classified according to the Common Terminology Criteria for Adverse Events. A Bayesian random-effects network meta-analysis was used to compare toxicity risks across regimens. Odds ratios (ORs) with 95% credible intervals (CrIs) were estimated, and surface under the cumulative ranking curve (SUCRA) values were used as descriptive ranking summaries interpreted alongside the corresponding comparative estimates. The protocol was registered in PROSPERO (CRD42024606194). Results Seventeen randomized trials including 8,946 patients and five ADCs—trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), trastuzumab deruxtecan (T-DXd), datopotamab deruxtecan (Dato-DXd), and ARX788—were analyzed. SG and T-DXd showed the least favorable hematologic safety profiles, with SUCRA values for anemia/neutropenia of 22.6%/17.4% and 12.0%/27.0%, respectively. T-DM1-based regimens had the highest risk of thrombocytopenia. For gastrointestinal toxicities, SG ranked worst for diarrhea (SUCRA 6.0%), whereas T-DXd was associated with higher risks of nausea (2.2%), vomiting (7.9%), and decreased appetite (8.6%). In analyses of SAEs, SG had the highest rates of anemia (11.7%) and neutropenia (8.5%), while gastrointestinal SAEs occurred more frequently with T-DXd. Conclusions This network meta-analysis highlights clinically meaningful differences in ADC safety profiles and may help guide individualized toxicity management in breast cancer.

Okazaki fragment maturation requires efficient removal of RNA primers to form a continuous lagging strand, yet how mismatched primers introduced by error-prone primase are corrected remains unresolved. Here, we show that physiological levels of reactive oxygen species (ROS) initiate a redox-dependent mechanism that drives ADAR1-mediated adenosine-to-inosine (A-to-I) editing. Oxidation triggers ADAR1 dimerization at replication forks, enhancing RNA editing of mismatched primers—particularly those caused by ATP misincorporation on d(T+C)-rich centromeric DNA. This A-to-I editing step facilitates more efficient RNA primer degradation by RNase H2, thereby ensuring proper Okazaki fragment maturation. Disruption of ADAR1 oxidation results in increased unligated Okazaki fragments, single-stranded gaps and double-strand breaks, most prominently at centromeres. These findings reveal a role for ROS in safeguarding lagging-strand synthesis by coupling ADAR1 oxidation-induced A-to-I RNA editing to replication fork stability. Chen et al. show that redox signals activate ADAR1 to fix faulty RNA pieces during DNA copying, ensuring smooth replication and protecting genome stability.

BACKGROUND:Partial breast irradiation (PBI) is an effective treatment for early-stage breast cancer. However, evidence comparing different PBI modalities is limited. METHODS:This trial emulation uses electronic health records from a multi-state large tertiary health system. Three PBI modalities were compared: proton radiation therapy, photon radiation therapy, and applicator-based brachytherapy. Inverse probability weighting (IPW) was used to balance confounders. The primary outcome was ipsilateral breast recurrence (IBR). RESULTS:Between 2013 and 2023, 1041 women with early-stage breast cancer were treated with PBI. Of these, 1026 patients were included in the analyses. The median age was 66 years; 22.51% had ductal carcinoma in situ (DCIS), and 97.56% were estrogen receptor positive. With median follow-up of 38.2 months, the rate of IBR in the overall group was 3.05% (95% confidence interval [CI] = 1.99% to 4.65%) at 3 years. After IPW, compared with photon PBI, the hazard ratio for IBR for proton PBI was 2.11 (95% CI = 0.70 to 6.33) and for brachytherapy, 3.86 (95% CI = 1.39 to 10.69). Compared with proton PBI, the hazard ratio for IBR for brachytherapy was 1.83 (95% CI = 0.88 to 3.81). IBR risk was similar across PBI modalities for patients with tumor size ≤ 10 mm and in patients treated for DCIS. Among patients with tumor size >10 mm, the hazard ratio for IBR for brachytherapy was 7.64 (95% CI = 1.64 to 35.58) and 3.59 (95% CI = 1.22 to 10.56) relative to photons and protons, respectively. CONCLUSION:PBI with applicator-based brachytherapy was associated with higher IBR than photon or proton PBI in patients with tumor size > 10 mm, suggesting the need for more careful PBI patient selection for this modality.

Our research uncovers a role for ATR in responding to ECM stiffness and promoting epithelial-to-mesenchymal transition (EMT) and metastasis. ATR, when deubiquitinated and upregulated by USP21 under enhanced ECM stiffness conditions, phosphorylates the nuclear protein SUN2, which promotes β-catenin nuclear translocation and EMT. ATM-mediated EMT promotes polymorphonuclear myeloid-derived suppressor cell recruitment and inhibits CD103+ dendritic cells, fostering an immunosuppressive tumor milieu. ATR inhibition disrupts this malignant cascade by promoting mesenchymal-to-epithelial transition to enhance antitumor immunity and mitigate metastases. Consistently, circulating HLA-DR+ dendritic cells were also enhanced following treatment with the ATR inhibitor berzosertib in patients with therapeutically resistant early-stage breast cancer. Our data suggest that ATR-targeted therapy may be optimized by considering both DNA damage-dependent and EMT-inducing effects of ATR.

OBJECTIVE:Proton minibeam radiation therapy (pMBRT) is a novel spatially fractionated radiation therapy technique that offers improved tumor control and reduced normal tissue toxicity. However, its clinical translation has been hindered in part by limited field sizes, low dose rates, and complex manufacturing. This work describes the design, manufacturing, and commissioning of a novel divergent pMBRT collimator along with accessory components to maximize its versatility and facilitate clinical implementation. APPROACH:The collimator geometry, including slit width, center-to-center (CTC) spacing, thickness, divergence, and field size, was optimized using TOPAS Monte Carlo (MC) to maximize surface peak-to-valley dose ratio (PVDR) while maintaining uniform target coverage. The collimator was constructed using brass plates held by aluminum side holders. Commissioning measurements with a PTW Bragg peak chamber and EBT4 radiochromic film were compared to TOPAS and an in-house fast GPU-based MC simulation. Ancillary equipment consisting of lead foils, range shifters, custom apertures, and secondary pMBRT collimators were characterized in tandem. MAIN RESULTS:An optimized divergent pMBRT collimator with 0.5 mm slit width, 2.0 mm CTC distance, and 40 mm thickness produced a surface PVDR of 4.8 while preserving quasihomogeneous dose in the 6-14 cm depth region. Measured dose profiles demonstrated valley dose agreement within 3% for both TOPAS and GPU-based MC predictions after the simulated collimator geometry was refined to match Bragg-peak chamber average dose measurements. The onset of the homogeneous dose region was shifted toward shallower depths by using thin lead foils, without significantly impacting entrance PVDR. Apertures sharpened penumbra and enhanced peripheral PVDR. A dual collimator approach produced 2D pinhole dose arrays that resulted in valley doses from MC simulations and film measurements agreeing within ~5%. SIGNIFICANCE:We demonstrated a practical low-cost, large-area divergent physical pMBRT collimation system with validated MC modeling. In addition, we introduce complementary accessories that substantially expand system versatility to facilitate clinical implementation.

PURPOSE:To expand preclinical efforts aimed at understanding the unique radiobiology of high linear energy transfer alpha particles and their implications for cancer therapy, robust, accessible, and high-throughput in vitro alpha irradiation platforms are needed. Such platforms must be extensively characterized and validated to ensure rigor and reproducibility. Here, we describe the construction and dosimetric characterization of a benchtop in vitro alpha irradiation platform using an americium 241 (241Am) source. METHODS AND MATERIALS:A square foil with embedded 241Am was used as the alpha source (activity 3.3785 mCi). The source was secured in the roof of a custom housing incorporating a 3-dimensional printed microcapillary array collimator to exclude large-angle alpha particles, thereby narrowing the energy spectrum and improving homogeneity. A movable shelf accommodates cells grown on glass slides at variable distances from the source. Dosimetric characterization included direct measurement of dose homogeneity, source self-attenuation, energy spectra, absorbed dose, and dose rate. RESULTS:The 241Am source, when used in conjunction with the microcapillary array, provided a spatially uniform and geometrically stable irradiation field. The mylar entrance window resulted in predictable shifting and broadening of the alpha particle energy spectra. Absorbed dose and dose-rate measurements (5.815-7.721 mGy/s) demonstrated the feasibility of controlled in vitro alpha particle irradiation studies. CONCLUSIONS:We established a turnkey, low-cost in vitro alpha irradiation platform suitable for high-throughput preclinical studies. The homogeneity, alpha particle energy spectra, absorbed dose, and dose rate were characterized and validated through direct measurements. Given the approximately 432-year half-life of 241Am, this platform will provide stable and reliable dose rates for decades, facilitating long-term radiobiological investigations.

Proton therapy has emerged as an important technique for locally advanced breast cancer (LABC), driven primarily by the need to reduce cardiopulmonary dose during comprehensive nodal irradiation, particularly when the internal mammary chain is targeted. Since the first clinical proton experience in patients with LABC and unfavorable cardiac anatomy in 2010, proton radiotherapy for LABC has evolved considerably: delivery technique has progressed from passive scattering and uniform scanning to pencil beam scanning and intensity-modulated proton therapy, while breast radiation oncology overall has shifted from field-based to volumetric, contour-driven planning. X, the first large prospective randomized trial comparing proton and photon regional nodal irradiation, completed accrual in 2024 (n=1,239); its 2025 health-related quality-of-life analysis showed similarly excellent patient-reported outcomes in both arms, while the trial's primary endpoints of loco-regional control and major cardiac events remain pending. Beyond X, most published experience remains single-institutional and technically heterogeneous. This critical review examines the historical development, technical evolution, and clinical application of proton therapy for LABC, with attention to contouring philosophy, robustness evaluation, and optimization of normal tissue-related side effects. Because proton plans are more sensitive to contour accuracy, setup, and range uncertainty than photon plans, and because proton entrance-dose behavior differs fundamentally from the photon skin-sparing effect, target delineation and plan robustness assessment require deliberate, disease-specific decision-making. We provide practical guidance for radiation oncologists, physicists, and dosimetrists, particularly those at centers early in their proton breast experience, and outline priorities for standardized reporting as long-term X outcomes mature.

PURPOSE:Pencil beam scanning (PBS) proton therapy enables highly conformal dose distributions and is increasingly used for postmastectomy radiation therapy (PMRT) to reduce cardiopulmonary exposure. However, implant-based reconstruction (IBR) in the setting of PMRT remains susceptible to capsular contracture, and the potential contribution of elevated linear energy transfer (LET) in PBS has not been well characterized. This study aimed to investigate the combined effects of dose and dose-averaged linear energy transfer (LETd) on capsular contracture after proton PMRT and to derive preliminary, exploratory volume cutoffs of dose-LET volume constraints (DLVCs). METHODS:We conducted a retrospective case-control study of consecutive breast cancer patients who underwent mastectomy followed by implant-based reconstruction and conventionally fractionated proton PMRT (50 Gy in 25 fractions) between 2015 and 2021. Patients who developed Baker grade III-IV capsular contracture were identified and matched 1:2 with controls using nearest-neighbor matching based on clinical and pathological variables. Dose-LET volume histograms (DLVHs) were calculated for peri-implant tissue (5-mm shell around the implant). Generalized linear mixed-effects regression (GLMER) was employed to identify DLVH indices significantly associated with capsular contracture. Redundant indices were removed using Spearman correlation analysis. DLVCs were derived from receiver operating characteristic (ROC) analysis and evaluated using a support vector machine (SVM)-based normal tissue complication probability (NTCP) model with leave-one-out cross-validation. RESULTS:Among 145 consecutive patients, 8 developed capsular contracture and were matched to 16 controls. Three independent DLVH indices were significantly associated with capsular contracture (p<0.01): V(55.8 Gy[RBE=1.1], 2.2 keV/μm), V(50.3 Gy[RBE=1.1], 5.4 keV/μm), and V(32.8 Gy[RBE=1.1], 0.9 keV/μm). After Benjamini-Hochberg (BH) false discovery rate correction across all 4,096 DLVH indices, all three remained significant (q_BH = 0.052). The corresponding DLVCs were: V(55.8 Gy[RBE=1.1], 2.2 keV/μm) < 0.0017%, V(50.3 Gy[RBE=1.1], 5.4 keV/μm) < 0.0033%, and V(32.8 Gy[RBE=1.1], 0.9 keV/μm) > 96.98%. The SVM-based NTCP model achieved an area under the ROC curve (AUROC) of 0.867, with accuracy of 91.7%, sensitivity of 87.5%, and specificity of 93.8%. CONCLUSION:Capsular contracture following proton PMRT is significantly associated with the combined effects of dose and LETd in peri-implant tissue. The derived DLVCs represent exploratory candidate dosimetric constraints that warrant further investigation and prospective validation in breast cancer patients undergoing proton PMRT with implant-based reconstruction.

Background/Objectives: We performed a systematic review of preclinical literature on the use of high-LET particle therapy, DDRi, and/or immunotherapy specifically in pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, and carbon) or X-ray radiation either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICIs) in pMMR colorectal cancer models. Results: In total, 131 studies met the inclusion criteria, including 70 preclinical studies. These studies consistently demonstrate that high-LET radiation amplifies immunogenic cell death, increases cGAS-STING pathway activation, and enhances tumor antigen presentation, thereby fostering greater immune infiltration and systemic antitumor responses. Concurrent irradiation with DDRi enhances persistent DNA damage and cytosolic DNA accumulation. In murine models, high-LET therapies show excellent local control, with manageable toxicity profiles. Combination regimens with ICIs exhibit improved local control and elicit systemic antitumor immune responses. Conclusions: High-LET particle radiation and/or the use of concurrent DDRi with ICI have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increased response rates to immunotherapy. The clinical evidence will be reviewed in the companion manuscript.

BACKGROUND:Minibeam radiotherapy (MBRT) is a spatially fractionated technique delivering alternating submillimeter high-dose peak and low-dose valley regions using orthovoltage x-rays. Preclinical studies demonstrate normal tissue sparing and antitumor activity, but clinical data are limited. Following a prior report of commissioning and treatment in two patients, we report the first clinical series evaluating clinical outcomes with MBRT for superficial malignancies. METHODS:Patients with superficial cutaneous and soft tissue malignancies were treated with MBRT at a single institution using a clinical orthovoltage unit and tungsten collimators producing 0.5-mm beams spaced 1.1 mm center-to-center. Cumulative incidence functions were used to estimate local progression. Toxicity was graded by CTCAE v5.0. RESULTS:Thirty-six patients with 46 lesions were treated between December 2023 and August 2025; 85% received MBRT alone. Median follow-up was 15.1 months. Median peak and valley doses per fraction were 25.9 Gy and 3.4 Gy; median number of fractions was 2. Patients were heavily pretreated, with 90% receiving ≥2 prior systemic therapies and 43% prior radiation. Symptomatic improvement occurred in 86%. Among 40 evaluable lesions, complete response occurred in 22.5%, partial response in 25%, and stable disease in 45%. Twelve-month local progression was 11% overall and 8% for MBRT alone. Documented abscopal responses occurred in 11% without systemic therapy changes. Grade 1-2 dermatitis occurred in 61%; two grade 3 adverse events occurred in patients with baseline tissue compromise. No grade 4-5 toxicities were observed. CONCLUSIONS:MBRT is well tolerated and yielded encouraging symptomatic benefits and local control in treatment-refractory superficial malignancies.

e15015 Background: Antibody-drug conjugates (ADCs) have demonstrated significant efficacy in treating patients with breast cancer. However, the toxicity variations between these agents are not yet thoroughly elucidated. This study aims to systematically compare the toxicity profiles of various ADCs used in breast cancer therapy to better inform clinical decision-making. Methods: We conducted a systematic review of randomized controlled trials (RCTs) published by September 2024. Treatment-related adverse events (TRAEs) of the investigational ADCs and standard of care control were classified into systemic categories based on Common Terminology Criteria for Adverse Events. Bayesian models were employed to facilitate the indirect comparisons of TRAEs associated with different ADCs and reported using surface under the cumulative ranking curve (SUCRA) values. The study protocol was prospectively registered on PROSPERO (CRD42024606194). Results: A total of 9307 patients in 17 RCTs of five different ADCs (ado-trastuzumab emtansine [T-DM1], sacituzumab govitecan [SG], trastuzumab deruxtecan [T-DXd], datopotamab deruxtecan [Dato-DXd], and ARX788) were included. SG and T-DXd monotherapy were associated with the highest risk of neutropenia/anemia, with SUCRA values of 11.2%/26.7%, and 20.7%/17.1%, respectively. T-DM1-containing regimens had the highest incidence of thrombocytopenia, which was exacerbated when combined with chemotherapy compared to monotherapy. In terms of gastrointestinal (GI) toxicities, SG was associated with the highest risk of diarrhea, followed by comparable risks between T-DM1 combined with chemotherapy and anti-HER2 and chemotherapy combined with dual anti-HER2 therapy. T-DXd was associated with a relatively higher incidence of vomiting (9.5%), while the highest risk of nausea was seen with chemotherapy with dual anti-HER2 therapy and T-DXd. SG and T-DXd were more likely to cause fatigue, decreased appetite, and dermatological disorders, including alopecia, rash, and pruritus, while T-DM1 combined with anti-HER2 therapies was linked a higher risk of pyrexia. T-DM1-containing regimens were also related to liver function test abnormalities, musculoskeletal and neurological disorders. Dato-DXd was associated with a higher risk of fatigue and dermatological toxicities, while ARX788 was associated with the least hematological and GI TRAEs. Conclusions: This Bayesian network meta-analysis highlights significant variability in TRAEs among different ADCs in breast cancer therapy. T-DM1 was primarily associated with thrombocytopenia and hepatic toxicities, while SG and T-DXd were associated with neutropenia, anemia, GI disorders, and dermatological TRAEs. Our findings may help with selection of ADC therapies for patients with breast cancer, facilitating personalized approaches to minimize treatment-related toxicities.

During DNA replication, the replisome must remove barriers and roadblocks including the transcription machinery1,2. Transcription-replication conflicts (TRCs) occur when there are collisions between the replisome and transcription machinery, and are increasingly recognized as an important source of mammalian genome instability3. How cells facilitate replisome bypass at sites of TRCs is incompletely understood. Here we show that the CUL3-KCTD10 E3 ligase senses TRCs and promotes remodelling of the RNA polymerase complex to allow replisome bypass. We found that the substrate adaptor KCTD10 interacts with the replisome and the transcription machinery and regulates both in unstressed conditions. These bivalent interactions allow KCTD10 to detect co-directional TRCs and facilitate higher-order assembly of KCTD10 complexes that recruit CUL3 to induce the ubiquitination and removal of the RNA polymerase factor TCEA2. In the absence of KCTD10, there is increased retention of TCEA2 and the RNA polymerase complex, causing an accumulation of TRCs and increased DNA damage. Our results demonstrate how replication can proceed through transcriptionally active regions, utilizing a unique bridging function of the CUL3-KCTD10 complex. These findings provide a framework for how the coordination between transcription and replication may contribute to the maintenance of genome stability.

Background: Radiation dermatitis (RD) is a frequent side effect and source of morbidity in patients receiving radiation treatment (RT) for breast cancer (BC), particularly for those undergoing post-mastectomy radiation (PMRT). The Alliance A221803 phase III randomized trial investigated the potential of Mepitel Film (MF) to mitigate RD in this at-risk patient population. We hypothesized that MF would reduce the severity of RD compared to institutional standard of care (SoC). Methods: Patients undergoing conventionally fractionated PMRT for non-inflammatory BC were randomized in a 2:1 fashion to receive either MF or institutional SoC. Stratification factors included patient body mass index (BMI) (< 25; 25-29.99; and ≥ 30), planned RT bolus (yes; no), planned RT boost (yes; no), and the presence or absence of reconstruction. The primary endpoint was the difference in area under the curves (AUCs) estimated from the repeated measures (means) mixed model using the patient-completed symptom scale component of the modified Radiation-Induced Skin Reaction Assessment Scale (mRISRAS) weekly during RT, 1-2 weeks after the end of RT (EoT), and at 3 months post-RT between the two arms controlling for stratification factors. The primary analysis included the first 192 assessable patients. Secondary endpoints included non-blinded provider component of the mRISRAS score, the combined (patient symptom scale and provider component) mRISRAS score, and acute adverse events (AEs) by CTCAE V5.0. This trial is registered on ClinicalTrials.gov (NCT04989504). Results: Between July 26, 2022 and January 4, 2024, 216 patients enrolled, with 143 assigned to MF and 73 to SoC. Stratification factors were balanced. Forty-five (21%) out of 216 enrolled patients were planned to have boost, 140 (65%) reconstruction, 75 (35%) planned bolus, and BMI was < 25 (26%), 25-29.99 (31%), and ≥30 (43%). Eight patients in the SoC arm withdrew consent prior to RT, leaving 65 patients in the SoC and 143 patients in the MF arm in the modified intention-to-treat analysis. Median age was 53 years. Eight or 9 survey timepoints were collected depending on receipt of boost, with a median of 8 mRISRAS surveys completed per patient. The estimated AUC was 45.10 in the SoC arm and 33.88 in the MF arm, with a difference in AUC (MF-SoC) of -11.22 (95% CI: -19.90, -2.54; p=0.012), meeting the primary endpoint of a significant reduction in patient-reported RD with MF compared with SoC. The improvement was observed across all stratification factors. In a pre-specified analysis, a statistically significant arm × timepoint interaction effect was seen, showing that patient-reported mRISRAS scores were lower with MF during RT at week 4, 5, and 6 of RT as well as at 7-14 days after the EoT (p = 0.0267). The combined patient and provider mRISRAS scores also identified less RD with MF, with a difference in AUC of -16.10 (p =0.011). The reduction in AUC with MF for unblinded provider mRISRAS scores was not statistically significant (AUC difference [MF-SoC -3.65 [95% CI: -9.35, 2.05, p=0.21]). Grade 2 at least possibly related or grade 3+ regardless of attribution RD was reduced with MF (44.6% in SoC, 25.2% in MF, p=0.005), whereas there was no significant difference in acute acneiform rash (1.54% in SoC vs. 1.4% in MF, p=0.94), pruritus (6.2% in SoC, 9.1% in MF, p=0.47), or skin infection (0% in SoC, 4.2% in MF, p=0.09). No grade 4 or 5 adverse events (AEs) were reported. Long-term follow-up is ongoing for evaluation of chronic AEs and reconstruction outcomes. Conclusions: Mepitel Film significantly reduces RD compared to SoC in patients undergoing RT for breast cancer. These findings support the use of MF as a new SoC option for RD prevention in patients undergoing PMRT. Support: U10CA180821, UG1CA189823; U10CA180868 (NRG Oncology); https://acknowledgments.alliancefound.org. Citation Format: Mepitel Film for the Reduction of Radiation Dermatitis in Post-mastectomy Radiation Therapy: Results from Alliance A221803: A Multicenter Phase III Randomized Clinical Trial. Mepitel Film for the Reduction of Radiation Dermatitis in Post-mastectomy Radiation Therapy: Results from Alliance A221803: A Multicenter Phase III Randomized Clinical Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr RF3-06.

Background: Evidence supporting exercise stress echocardiography (ESE) for breast cancer survivors treated with chest radiotherapy is scarce, and its association with clinical outcomes has not been evaluated. Objectives: The objectives of the were to evaluate the prognostic value of ESE for breast cancer survivors treated with chest radiotherapy and to assess the relationship of radiotherapy with cardiovascular death and nonfatal myocardial infarction (CVD + NFMI), major adverse cardiac events (MACE), and all-cause mortality. Methods: For this retrospective study, we included 507 breast cancer survivors treated with chest radiotherapy who underwent ESE from 2000 through 2020. Results: The median (IQR) follow-up was 7.8 (4.9-10.8) years; the mean (SD) age at ESE was 65.9 (9.9) years and the median time from radiotherapy to ESE was 4.3 (2.0-7.4) years. Patients completed 7.33 (2.03) metabolic equivalents. Seventy-six patients had ischemia on ESE. They were older than those with normal ESE (67.3 vs 65.6 years) and had more atrial fibrillation (14.5% vs 6.3%) and chronic obstructive pulmonary disease (5.3% vs 0.7%). There were 35 CVD + NFMI, 61 MACE, and 80 deaths. Ischemic ESE was associated with an increased risk of CVD + NFMI (HR: 2.25; 95% CI: 1.05-4.76) and MACE (HR: 3.62; 95% CI: 2.07-6.32) even after adjusting for cardiovascular risk factors, metabolic equivalents achieved, and cardiotoxic chemotherapy; the risk of all-cause mortality in these patients was not increased (HR: 1.33; 95% CI: 0.78-2.26). Conclusions: An ischemic ESE predicts CVD + NFMI and MACE in patients with breast cancer treated with chest radiotherapy, independent of cardiovascular comorbid conditions and aerobic capacity. These patients should have closer follow-up and intense strategies to reduce cardiovascular risk.