This study assessed an instructional video for patient education on respiratory gating in breast cancer radiotherapy. Among 476 patients, the video-based workflow increased lung volumes and the proportion undergoing respiratory gating, while maintaining high target coverage and low doses to organs of interest, supporting the feasibility of using video instruction to achieve effective gating.

PURPOSE:Proton therapy (PT) is associated with favorable dosimetric characteristics compared with photon radiation therapy (γRT) in invasive breast cancer; however, clinical evidence on acute toxicity remains limited. This study aimed to compare acute treatment-related side effects between moderately hypofractionated PT and γRT in breast cancer. METHODS AND MATERIALS:The Danish Breast Cancer Group Proton trial-acute side effects was a preplanned substudy of the national, phase 3 randomized trial, the Danish Breast Cancer Group Proton trial. Patients with invasive breast cancer or ductal carcinoma in situ scheduled for adjuvant radiation therapy (RT), who were expected to receive a high cardiac and/or pulmonary dose based on γRT planning computed tomography scan, were randomized 1:1 to PT or γRT. Acute side effects were prospectively assessed during RT and up to 6 months posttreatment. Outcomes included skin-related side effects, respiratory symptoms, dysphagia, fatigue, and arm/shoulder side effects. RESULTS:A total of 167 patients (186 treated breasts) were included (PT 84 and γRT 83). Skin-related side effects peaked at week 5, with higher grade 2 to 3 dermatitis (71% PT vs 20% γRT), pruritus (20% vs 5%), and local pain (17% vs 4%) after PT compared with γRT. All skin-related grade 2 to 3 side effects were transient, resolving to grade 0 to 1 within 2 to 4 weeks after peaking. Respiratory symptoms, dysphagia, and fatigue were mild and similar between groups. Clinically relevant arm/shoulder morbidity was rare. No treatment discontinuations because of side effects were observed. CONCLUSIONS:Acute side effects after breast cancer RT were primarily skin-related, higher but transient after PT compared with γRT. Non-skin-related side effects, including respiratory symptoms, fatigue, and arm/shoulder morbidity, were comparable between PT and γRT. These prospective data, using modern techniques and moderate hypofractionation, suggest that PT is a feasible and clinically acceptable treatment approach for adjuvant treatment of invasive breast cancer or ductal carcinoma in situ, while acknowledging the higher incidence of transient acute skin-related side effects.

Moderately hypofractionated radiotherapy is increasingly replacing conventional schedules (2 Gy/fraction) in adjuvant breast cancer treatment. Tumor-infiltrating lymphocytes (TILs) have emerged as a prognostic biomarker, particularly in aggressive subtypes, but their role in node-negative patients and their relation to radiotherapy fractionation remain unclear. Immune infiltration in primary tumors was examined in the randomized Danish Breast Cancer Group HYPO trial, including 1329 node-negative breast cancer patients treated with breast-conserving surgery and randomized to standard fractionated (50 Gy/25 fractions) versus hypofractionated (40 Gy/15 fractions) radiotherapy. A case-cohort design included 349/1329 patients for histopathological analyses of TILs and immune cell subsets (CD8, CD4, FOXP3, CD68, CD11c). Associations with the primary endpoint, overall mortality (OM), were evaluated using multivariable flexible parametric survival models. Predictive effects of immune markers on fractionation were assessed through interaction tests. Median follow-up was 7.9 years. High TILs (cut-off ≥ 30

Background. With improved early detection and treatment of breast cancer, survival rates have significantly improved. However, many long-term survivors experience disease- and treatment-related late effects, impacting their quality of life. Traditional follow-up models are resource-intensive and increasingly unsustainable. Digital follow-up systems incorporating patient-reported outcomes (PROs) may offer a scalable, individualized solution. This study evaluates the feasibility of DCCL-PRO, a mobile application designed to support personalized, need-based follow-up care for breast cancer survivors. The app aims to facilitate early identification of recurrence or late effects, reduce unnecessary hospital visits, improve self-management, and support adherence to adjuvant therapy. Materials and Methods. The DCCL-PRO smartphone application was developed to collect PRO data via validated questionnaires at defined intervals during treatment and follow-up. Patients receive real-time feedback, and alerts are issued to clinicians via a secure web-based interface. Feasibility was assessed through usability testing, patient engagement metrics, and real-world implementation in Danish breast cancer follow-up programs. Results. Usability testing (n=30) revealed high satisfaction, with mean scores of 8.5/10 for content and 9.0/10 for feedback. In a real-world cohort (n=514), 70% of newly diagnosed patients actively used the app, indicating satisfactory adoption and engagement. Conclusion. DCCL-PRO demonstrates feasibility as a digital, PRO-based follow-up system that can enhance patient engagement, facilitate early detection of complications, and improve healthcare efficiency by enabling personalized, need-based follow-up, thus reducing unnecessary hospital visits. Further studies are needed to assess its long-term impact on clinical outcomes and effectiveness compared to conventional follow-up methods.

BACKGROUND AND PURPOSE:Adjuvant loco-regional radiotherapy reduces recurrence risk and enhances survival in early-stage breast cancer. The ESTRO consensus guideline on target volume delineation for elective radiotherapy of early-stage breast cancer, published in 2015, sought to standardise contouring practices. In the DBCG Skagen Trial 1, all clinical target volume (CTV) delineations followed the ESTRO guideline, allowing pre-planned prospective validation. This study aimed to characterise the loco-regional recurrence (LRR) pattern in accordance with target delineation as per the ESTRO guideline. MATERIALS AND METHODS:DBCG Skagen Trial 1 enrolled 2,963 patients (2,908 in the intention-to-treat cohort). LRR, with or without concurrent distant recurrence, were identified from imaging and medical records, and categorised as inside the CTV, marginal miss, or distant recurrence relative to the ESTRO-defined CTVs. RESULTS:At median follow-up of 5.2 years (IQR 4.1-6.7), 78 patients developed LRR: 41 isolated LRR and 37 with concurrent distant recurrence. Among the 78 patients with LRR, 74 (95%) had recurrences located within the ESTRO-defined CTVs and were planned to receive the full prescribed dose. All local recurrences were within the CTVp, and all but three patients had regional recurrences within the CTVn. Only three marginal misses were identified. CONCLUSION:LRR in the DBCG Skagen Trial 1 occurred almost exclusively within the ESTRO-defined CTVs, providing prospective validation of the guideline, without evidence suggesting a need for modification of target volumes.

Background and purpose:Radiation-induced fibrosis affects women having undergone post-lumpectomy radiotherapy to a varying degree and remains a significant late morbidity for breast cancer patients. While Single Nucleotide Polymorphisms (SNPs) have been linked to fibrosis after radiotherapy (RT), the genetic architecture remains incompletely understood. We aimed to identify new genetic variants in a cohort of early breast cancer patients representing two cohorts treated within the Danish Breast Cancer Group (DBCG) protocols. Material and methods:A genome-wide association study (GWAS) was conducted on 869 patients treated with lumpectomy and adjuvant radiotherapy within the DBCG trials hypo- versus normofractionated radiotherapy trial, DBCG-HYPO, and the DBCG partial versus whole breast irradiation trial, DBCG-PBI. After genotyping and imputation, we tested associations between common variants and grade 2-3 fibrosis (LENT-SOMA) using a per-risk allele log-additive model. The threshold for genome-wide significance was set at P < 5 × 10-8. Results:After adjusting for principal component outliers, we identified a suggestive association on chromosome 10 (P = 5.90 × 10-8). The lead variant was rs75542274. While this locus approached the pre-defined genome-wide significance threshold, no other variants reached significance. Conclusion:This exploratory GWAS identified a potential susceptibility locus for radiation-induced fibrosis on chromosome 10. Given the near-significant nature of this finding, independent validation or meta-analysis is required to confirm the role of rs75542274 in the development of RT-induced fibrosis. Further analysis is warranted.

LBA503 Background: Axillary lymph node dissection (ALND) causes arm-related morbidity. The SENOMAC trial evaluates whether the omission of completion ALND in patients with 1-2 sentinel lymph node (SLN) macrometastases is oncologically safe. It differs from previous trials in size and the inclusion of larger tumors and patients receiving mastectomy. Methods: SENOMAC (NCT02240472) is an international non-inferiority trial. Adult patients with primary invasive, clinically node-negative T1-3 breast cancer and up to two SLN macrometastases were randomized 1:1 to completion ALND (standard) or its omission (intervention). Adjuvant treatment followed standards of care. The primary endpoint was overall survival (OS), requiring 190 deaths to conclude non-inferiority (upper one-sided 90% CI for the hazard ratio < 1.44) with ALND as the reference group. The secondary endpoint breast cancer-specific survival (BCSS) required 66 breast cancer deaths. Patient-reported outcomes were recorded 1, 3, and 5 years after randomization by the questionnaires Lymph-ICF (arm morbidity), EORTC QLQ-C30 and BR23 (health-related quality of life). Results: From 1/2015 to 12/2021, 2766 patients were randomized in 5 countries. The per-protocol population comprised 2540 patients (1205 randomized to ALND and 1335 to its omission). The median follow-up was 60.1 months (1.5-122.7 months). Questionnaire response rates were 81.3% and 74.6% at 3 and 5 years, respectively. Overall, 196 patients died, 75 of whom due to breast cancer. Five-year OS was 93.4% (95% CI 91.9%-94.9%) in the ALND and 94.4% (95% CI 93.1%-95.7%) in the omission group, with a country-adjusted hazard ratio of 0.84 (95% CI 0.64-1.12). Five-year BCSS was 97.3% (95% CI 96.4%-98.3%) in the ALND and 97.8% (95% CI 97.0%-98.6%) in the omission group, with a country-adjusted hazard ratio of 0.86 (95% CI 0.55-1.34). Both endpoints fell significantly (p = 0.238 for OS and p = 0.504 for BCSS) below the pre-specified non-inferiority margin. Arm physical function according to the Lymph-ICF questionnaire was significantly better in the omission than the ALND group with a clinically relevant mean score difference of 6.14 at 3 years (95% CI 5.00-7.43, p < 0.001) and 5.71 at 5 years (95% CI 4.46-7.25, p < 0.001). Similarly, arm symptoms according to EORTC QLQ-BR23 were significantly more pronounced in the ALND than the omission group both after 3 (mean score 20.80+/-21.24 versus mean score 10.83+/-15.48, p < 0.001) and after 5 years (mean score 19.40+/-21.07 versus mean score 9.31+/-15.58, p < 0.001). Global health-related quality of life did not show any statistically significant differences after 3 and 5 years. Conclusions: Omission of completion ALND after a positive SLN biopsy is oncologically safe and mitigates postoperative patient-reported arm morbidity. Clinical trial information: NCT02240472 .

BACKGROUND:Postoperative lymph node irradiation can affect shoulder morbidity in breast cancer patients, yet widely accepted dose-volume constraints for the shoulder joint are lacking. The SENOMAC trial randomized patients with breast cancer and 1-2 sentinel lymph node (SLN) macrometastases to axillary lymph node dissection (ALND) or SLN biopsy only. We aimed to analyze the association between the radiation dose to the shoulder joint and patient-reported arm morbidity one and three years after surgery using SENOMAC data. METHODS:Radiotherapy plans from 868 Swedish SENOMAC patients randomized 2015-2019 were collected. The humeral head was auto-segmented, and a 1 cm margin added to represent the shoulder joint. Arm morbidity was assessed using the Lymph-ICF questionnaire, focusing on questions regarding physical arm function and shoulder-related mobility tasks. RESULTS:The radiation dose was evaluable for 386 patients receiving ALND and 421 receiving SLN biopsy. The dose distribution to the shoulder joint was similar in both study groups. In the SLN group, a higher near-maximum dose (D0.5cc) was associated with significantly worse arm morbidity scores three years after surgery, particularly among patients treated with breast-conserving surgery. No association was found in the ALND group. No dose thresholds for development of arm/shoulder related side effects could be identified. CONCLUSION:Our results indicate a possible association between maximum radiation dose to the shoulder joint and subsequent side effects. Extended follow-up within SENOMAC will provide further insights into the incidence of arm morbidity in relation to radiotherapy dose over time.

Purpose:Registration of carcinoma in situ (CIS) lesions in the national Danish Breast Cancer Group (DBCG) database is incomplete. We aimed to develop and validate a computer-based algorithm designed to identify patients with pure CIS of the breast, defined as CIS without concurrent breast cancer (BC), and with no history of BC or ipsilateral CIS. A secondary aim was to assess the completeness of CIS registration in the DBCG database. Patients and Methods:We developed an algorithm to identify patients diagnosed with pure CIS between 2008 and 2017 using Systematized NOmenclature of MEDicine codes from the Danish Pathology Registry (DPR). We manually reviewed pathology records of a subcohort from Aarhus University Hospital (AUH) to serve as reference standard. To test reproducibility, the algorithm was reapplied to DPR data spanning 2008 to 2023. Results:Between 2008 and 2017, 13,720 patients diagnosed with CIS of any kind were identified in the DPR. Of these, 1,581 patients were diagnosed at AUH, and 572 of those were manually confirmed as cases of pure CIS. The algorithm correctly classified 560 of these cases, corresponding to a sensitivity of 97.9% (95% CI: 96.3-99.3%). The positive predictive value of the algorithm for identifying pure CIS was 100.0% (95% CI: 99.3-100.0%). On a national level, the algorithm identified 4,302 patients with pure CIS between 2008 and 2017. Of those, 1,002 (23%) were not registered in the DBCG database. In the extended study population, 7,206 patients with pure CIS were identified, and 4,266 (99.2%) cases from the original study population were reclassified as pure CIS. Of 7,206 total patients, 1,827 (25%) were not registered in the DBCG database. Conclusion:Demonstrating high accuracy and reproducibility, the algorithm represents an optimal method for future identification of patients with pure CIS who are not registered in the DBCG database.

Purpose/Objective:Partial breast irradiation (PBI) is standard for selected relatively low-risk breast cancer patients, aiming to minimise late effects while maintaining local control. The Danish Breast Cancer Group (DBCG) RT Natural trial investigated whether PBI could be safely omitted in selected patients. Here, we report the radiotherapy quality assurance in the trial, evaluating target coverage and doses to organs of interest against protocol criteria. Material/Methods:Eligible patients were women ≥ 60 years with T ≤ 20 mm, unilateral, unifocal, node-negative, hormone receptor-positive, HER2-normal, non-lobular invasive breast cancer. Patients were randomised 1:1 to PBI (40 Gy in 15 fractions) versus no radiotherapy. Treatment plans for all patients treated with PBI were prospectively collected in a centralised DICOM-RT database and evaluated for protocol compliance. Results:Data from the 238 patients receiving PBI were analysed. Dose coverage was high, with median V95% of 100% for the tumour bed and CTVp_PBI and 98% for the PTVp_PBI. Only 1% had a CTVp_PBI V95% below the intended 95%, whereas 22% had a PTVp_PBI V95% <95%. No patients exceeded 110% of the prescribed dose. Dose conformity was good with median whole-breast V40Gy of 21%.Ipsilateral median mean lung dose was 1.52 Gy, and median mean heart dose 0.25 Gy left / 0.12 Gy right with no violation of dose guidance. Respiratory gating did not significantly affect lung or heart doses. Conclusion:PBI in the DBCG RT Natural trial provided robust target coverage with minimal high-dose volumes, and maintained low cardiac and pulmonary doses, consistent with protocol planning objectives.

High levels of tumor-infiltrating lymphocytes (TILs) are associated with improved survival after radiotherapy in breast cancer (BC) patients, particularly in estrogen receptor (ER)-negative disease. This study investigated the prognostic relevance of immune cell subsets in irradiated patients. Node-positive patients (N = 1307) from the Danish Breast Cancer Group internal mammary node (IMN)2 study were included, in which IMN irradiation (IMNI) was allocated by laterality. Tissue microarrays were stained with multiplex immunohistochemistry for CD8+, CD4+, and FOXP3+ T-cells, CD68+ macrophages, and CD11c+ dendritic cells. Digital image analysis quantified immune infiltration across spatial compartments. Prognostic associations with distant recurrence, breast cancer-specific mortality, and overall mortality (OM) were assessed using multivariable flexible parametric survival models, including ER-stratified analyses. T-cell infiltration demonstrated a strong inverse association with OM, with 12-year OM-risk decreasing from 42% in tumors with lowest CD8+ infiltration to 27% in those with highest (HR 0.52, 95% CI (0.36-0.76)). The association was strongest in the ER-negative subgroup. In ER-positive disease, prognostic benefit was observed at low-to-moderate infiltration. CD68+ and CD11c+ infiltration correlated with improved outcomes, but with weaker effects. Immune markers were not predictive of IMNI benefit. These findings demonstrate that T-cell subsets are strong prognostic markers in irradiated BC patients, especially in ER-negative disease.

Robust quality assurance (QA) of clinical trials in radiotherapy (RT) is paramount for minimising uncertainties in treatment delivery, thereby strengthening the statistical power of the study and increasing the likelihood of accurately answering the research question. As RT techniques evolve and become more complex, establishing an appropriate QA program for a specific clinical trial becomes increasingly challenging, highlighting the importance of clear and standardised recommendations. This study provide such recommendations for Principal Investigators (PIs) to consider when planning and conducting RT Quality Assurance (RTQA) for clinical trials. They arise from experiences with RTQA in the clinical trials conducted in the Danish Multidisciplinary Cancer Groups (DMCGs). The recommendations include a checklist to guide PIs in developing an effective RTQA program.

Background: Studies of the Danish Breast Cancer Group (DBCG)82bc cohort of high-risk breast cancer (BC) patients randomized to +/- postmastectomy radiotherapy (RT) showed that high levels of tumor-infiltrating lymphocytes (TILs) in treatment-naïve tumor predicts improved overall survival (OS), especially for patients with estrogen receptor-negative tumors (ER-) (doi: 10.1080/0284186X.2021.1989629). The association was mediated through distant tumor control rather than local control. We aimed to validate these findings in modernly treated, irradiated BC patients and to investigate the predictive value of TILs in terms of benefit from RT. Methods and Materials: Patients originated from the DBCG-IMN2 cohort (N=980), including node-positive (N+) BC patients with T1-T3 disease, treated between 2007-2014 with breast-conserving surgery or mastectomy, axillary dissection, and loco-regional RT. Irradiation of the internal mammary nodes (IMN-RT) was administered in 460 right-sided patients (47%), and 520 left-sided patients (53%) did not receive IMN-RT (IMN-RT allocated per laterality). All patients had systemic adjuvant therapy including taxanes, trastuzumab and letrozole. Formalin-fixed, paraffin-embedded treatment-naïve tumor tissue was collected from 980 patients. Stromal TILs were estimated on whole slide Hematoxylin & eosin-stained sections following international guidelines. Tumors were categorized into "low" and "high" TILs groups using a 30% cutoff. Endpoints included loco-regional recurrence (LRR), distant metastasis (DM), and OS. Kaplan-Meier and Aalen-Johansen estimators along with univariate Cox regression analysis were used for statistical evaluation. Results: Of the 980 patients, 798 (81%) had estrogen receptor-positive (ER+) tumors, whereas 182 (19%) had ER- tumors. TILs were successfully scored in 911 tumors, and among these, 737 (81%) had low TILs and 174 (19%) high TILs. Patients with ER-/low TILs tumors (N=88) had significantly worse OS compared to ER-/high TILs (N=76) with an adjusted Hazard Ratio (adj. HR) of 0.3 (95% CI: 0.2-0.6), and absolute reduction in OS at 10-years of 30% (47% vs. 77%). No significant difference in OS was observed among patients with ER+ tumors (adj. HR 0.9 (0.6-1.5)), and the interaction test between ER status and TILs was significant (p=0.006). A similar association was found for DM (adj. HR 0.3 (0.2-0.6)), where patients with ER-/low TILs tumors had a 24% absolute higher 10-year risk (42% vs. 18%) compared to ER-/high TILs. No significant difference in DM was observed among ER+ tumors (adj. HR 0.6 (0.4-1.1)). TILs did not impact LRR in patients with either ER- tumors (adj. HR 1.3 (0.3-5.5)) or ER+ tumors (adj. HR 3.2 (0.9-11.0)). The association between RT, TILs and OS as previously described in the DBCG82bc study was further validated since a predictive value of TILs in terms of IMN-RT was seen. Patients with low TILs and right-sided tumors, receiving IMN-RT, had an absolute improvement in OS at 10-years of 9% (79% vs. 70%) compared to patients who did not receive IMN-RT (adj. HR 0.7 (0.5-0.9)). For patients with high TILs, an absolute OS improvement at 10-years of 3% was non-significant (79% vs. 76%). Subdividing by ER status did not affect these results. Conclusions: This study validates previous findings in the DBCG82bc cohort, indicating a robust association between TILs and ER status in irradiated, N+ BC patients. It further supports that poorer OS in irradiated patients with low TILs is mediated through compromised distant tumor control rather than through local failure. The data suggests a predictive value of TILs in terms of IMN-RT, where the addition of IMN-RT was associated with improved OS in patients with low TILs. The results emphasize the potential of TILs as a biomarker in tailoring more personalized RT strategies for BC patients. Citation Format: Demet Özcan, Anders W.M. Nielsen, Jan Alsner, Else Maae, Mette H. Nielsen, Lars Stenbygaard, Lise B.J. Thorsen, Jens Overgaard, Birgitte V. Offersen, Trine Tramm. Validation of the association between TILs, ER status and benefit of radiotherapy in node positive, breast cancer patients: a DBCG study [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 RF2-05.