Prediction of Overall Disease Burden in (y)pN1 Breast Cancer Using Knowledge-Based Machine Learning Model.

BACKGROUND: We aimed to construct an expert knowledge-based Bayesian network (BN) model for assessing the overall disease burden (ODB) in (y)pN1 breast cancer patients and compare ODB across arms of ongoing trials. METHODS: Utilizing institutional data and expert surveys, we developed a BN model for (y)pN1 breast cancer. Expert-derived probabilities and disability weights for radiotherapy-related benefit (e.g., 7-year disease-free survival [DFS]) and toxicities were integrated into the model. ODB was defined as the sum of disability weights multiplied by probabilities. In silico predictions were conducted for Alliance A011202, PORT-N1, RAPCHEM, and RT-CHARM trials, comparing ODB, 7-year DFS, and side effects. RESULTS: In the Alliance A011202 trial, 7-year DFS was 80.1% in both arms. Axillary lymph node dissection led to higher clinical lymphedema and ODB compared to sentinel lymph node biopsy with full regional nodal irradiation (RNI). In the PORT-N1 trial, the control arm (whole-breast irradiation [WBI] with RNI or post-mastectomy radiotherapy [PMRT]) had an ODB of 0.254, while the experimental arm (WBI alone or no PMRT) had an ODB of 0.255. In the RAPCHEM trial, the radiotherapy field did not impact the 7-year DFS in ypN1 patients. However, there was a mild ODB increase with a larger irradiation field. In the RT-CHARM trial, we identified factors associated with the major complication rate, which ranged from 18.3% to 22.1%. CONCLUSIONS: The expert knowledge-based BN model predicted ongoing trial outcomes, validating reported results and assumptions. In addition, the model demonstrated the ODB in different arms, with an emphasis on quality of life.

Assessment of lymph node area coverage with total marrow irradiation and implementation of total marrow and lymphoid irradiation using automated deep learning-based segmentation.

BACKGROUND: Total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI) have the advantages. However, delineating target lesions according to TMI and TMLI plans is labor-intensive and time-consuming. In addition, although the delineation of target lesions between TMI and TMLI differs, the clinical distinction is not clear, and the lymph node (LN) area coverage during TMI remains uncertain. Accordingly, this study calculates the LN area coverage according to the TMI plan. Further, a deep learning-based model for delineating LN areas is trained and evaluated. METHODS: Whole-body regional LN areas were manually contoured in patients treated according to a TMI plan. The dose coverage of the delineated LN areas in the TMI plan was estimated. To train the deep learning model for automatic segmentation, additional whole-body computed tomography data were obtained from other patients. The patients and data were divided into training/validation and test groups and models were developed using the "nnU-NET" framework. The trained models were evaluated using Dice similarity coefficient (DSC), precision, recall, and Hausdorff distance 95 (HD95). The time required to contour and trim predicted results manually using the deep learning model was measured and compared. RESULTS: The dose coverage for LN areas by TMI plan had V100% (the percentage of volume receiving 100% of the prescribed dose), V95%, and V90% median values of 46.0%, 62.1%, and 73.5%, respectively. The lowest V100% values were identified in the inguinal (14.7%), external iliac (21.8%), and para-aortic (42.8%) LNs. The median values of DSC, precision, recall, and HD95 of the trained model were 0.79, 0.83, 0.76, and 2.63, respectively. The time for manual contouring and simply modified predicted contouring were statistically significantly different. CONCLUSIONS: The dose coverage in the inguinal, external iliac, and para-aortic LN areas was suboptimal when treatment is administered according to the TMI plan. This research demonstrates that the automatic delineation of LN areas using deep learning can facilitate the implementation of TMLI.

Estimating the risk and benefit of radiation therapy in (y)pN1 stage breast cancer patients: A Bayesian network model incorporating expert knowledge (KROG 22-13).

BACKGROUND: We aimed to evaluate the risk and benefit of (y)pN1 breast cancer patients in a Bayesian network model. METHOD: We developed a Bayesian network (BN) model comprising three parts: pretreatment, intervention, and risk/benefit. The pretreatment part consisted of clinical information from a tertiary medical center. The intervention part regarded the field of radiotherapy. The risk/benefit component encompasses radiotherapy (RT)-related side effects and effectiveness, including factors such as recurrence, cardiac toxicity, lymphedema, and radiation pneumonitis. These factors were evaluated in terms of disability weights and probabilities from a nationwide expert survey. The overall disease burden (ODB) was calculated as the sum of the probability multiplied by the disability weight. A higher value of ODB indicates a greater disease burden for the patient. RESULTS: Among the 58 participants, a BN model utilizing discretization and clustering techniques revealed five distinct clusters. Overall, factors associated with breast reconstruction and RT exhibited high discrepancies (24-34 %), while RT-related side effects demonstrated low discrepancies (3-11 %) among the experts. When incorporating recurrence and RT-related side effects, the mean ODB of (y)pN1 patients was 0.258 (range, 0.244-0.337), with a higher tendency observed in triple-negative breast cancer (TNBC) or mastectomy cases. The ODB for TNBC patients undergoing mastectomy without postmastectomy radiotherapy was 0.327, whereas for non-TNBC patients undergoing breast conserving surgery with RT, the disease burden was 0.251. There was an increasing trend in ODB as the field of RT increased. CONCLUSION: We developed a Bayesian network model based on an expert survey, which helps to understand treatment patterns and enables precise estimations of RT-related risk and benefit in (y)pN1 patients.

Assessment of Eligibility and Utilization of Accelerated Partial Breast Irradiation in Korean Breast Cancer Patients (KROG 22-15).

PURPOSE: We investigated the proportions of patients eligible for accelerated partial breast irradiation (APBI) among those with pT1-2N0 breast cancer, based on the criteria set by the American Society for Radiation Oncology (ASTRO), the Groupe Européen de Curiethérapie and the European Society for Radiotherapy and Oncology (GEC-ESTRO), the American Brachytherapy Society (ABS), and the American Society of Breast Surgeons (ASBS). Additionally, we analyzed the rate of APBI utilization among eligible patients. MATERIALS AND METHODS: Patients diagnosed with pT1-2N0 breast cancer in 2019 were accrued in four tertiary medical centers in Korea. All patients had undergone breast conserving surgery followed by radiotherapy, either whole breast irradiation or APBI. To determine which guideline best predicts the use of APBI in Korea, the F1 score and Matthews Correlation Coefficient (MCC) were determined for each guideline. RESULTS: A total of 1,251 patients were analyzed, of whom 196 (15.7%) underwent APBI. The percentages of eligible patients identified by the ASTRO, GEC-ESTRO, ABS, and ASBS criteria were 13.7%, 21.0%, 50.5%, and 63.5%, respectively. APBI was used to treat 54.4%, 37.2%, 27.1%, and 23.7% of patients eligible by the ASTRO, GEC-ESTRO, ABS, and ASBS criteria, respectively. The ASTRO guideline exhibited the highest F1 score (0.76) and MCC (0.67), thus showing the best prediction of APBI utilization in Korea. CONCLUSION: The proportion of Korean breast cancer patients who are candidates for APBI is substantial. The actual rate of APBI utilization among eligible patients may suggest there is a room for risk-stratified optimization in offering radiation therapy.

Concurrent Lapatinib With Brain Radiation Therapy in Patients With HER2+ Breast Cancer With Brain Metastases: NRG Oncology-KROG/RTOG 1119 Phase 2 Randomized Trial.

PURPOSE: Lapatinib plus whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) was hypothesized to improve the 12-week intracranial complete response (CR) rate compared with either option of radiation therapy (RT) alone for patients with brain metastases (BM) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer. METHODS AND MATERIALS: This study included patients with HER2+ breast cancer with ≥1 measurable, unirradiated BM. Patients were randomized to WBRT (37.5 Gy/3 wk)/SRS (size-based dosing) ± concurrent lapatinib (1000 mg daily for 6 weeks). Secondary endpoints included objective response rate (ORR), lesion-specific response, central nervous system progression-free survival, and overall survival. RESULTS: From July 2012 to September 2019, 143 patients were randomized, with 116 analyzable for the primary endpoint. RT + lapatinib did not improve 12-week CR (0% vs 6% for RT alone, 1-sided P = .97), or ORR at 12 weeks. At 4 weeks, RT + lapatinib showed higher ORR (55% vs 42%). Higher graded prognostic assessment and ≤10 lesions were associated with higher 12-week ORR. Grade 3 and 4 adverse event rates were 8% and 0% for RT and 28% and 6% for RT + lapatinib. CONCLUSIONS: The addition of 6 weeks of concomitant lapatinib to WBRT/SRS did not improve the primary endpoint of 12-week CR rate or 12-week ORR. Adding lapatinib to WBRT/SRS showed improvement of 4-week ORR, suggesting a short-term benefit from concomitant therapy.

Assessment of deep learning-based auto-contouring on interobserver consistency in target volume and organs-at-risk delineation for breast cancer: Implications for RTQA program in a multi-institutional study.

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

Developing prompts from large language model for extracting clinical information from pathology and ultrasound reports in breast cancer.

PURPOSE: We aimed to evaluate the time and cost of developing prompts using large language model (LLM), tailored to extract clinical factors in breast cancer patients and their accuracy. MATERIALS AND METHODS: We collected data from reports of surgical pathology and ultrasound from breast cancer patients who underwent radiotherapy from 2020 to 2022. We extracted the information using the Generative Pre-trained Transformer (GPT) for Sheets and Docs extension plugin and termed this the "LLM" method. The time and cost of developing the prompts with LLM methods were assessed and compared with those spent on collecting information with "full manual" and "LLM-assisted manual" methods. To assess accuracy, 340 patients were randomly selected, and the extracted information by LLM method were compared with those collected by "full manual" method. RESULTS: Data from 2,931 patients were collected. We developed 12 prompts for Extract function and 12 for Format function to extract and standardize the information. The overall accuracy was 87.7%. For lymphovascular invasion, it was 98.2%. Developing and processing the prompts took 3.5 hours and 15 minutes, respectively. Utilizing the ChatGPT application programming interface cost US $65.8 and when factoring in the estimated wage, the total cost was US $95.4. In an estimated comparison, "LLM-assisted manual" and "LLM" methods were time- and cost-efficient compared to the "full manual" method. CONCLUSION: Developing and facilitating prompts for LLM to derive clinical factors was efficient to extract crucial information from huge medical records. This study demonstrated the potential of the application of natural language processing using LLM model in breast cancer patients. Prompts from the current study can be re-used for other research to collect clinical information.

Patterns and Longitudinal Changes in the Practice of Breast Cancer Radiotherapy in Korea: Korean Radiation Oncology Group 22-01.

PURPOSE: We aimed to analyze contemporary practice patterns in breast cancer radiotherapy (RT) and assess longitudinal changes over five years in Korea. METHODS: In 2022, a nationwide survey was conducted among board-certified radiation oncologists. The survey consisted of 44 questions related to six domains: hypofractionated (HypoFx) whole breast RT, accelerated partial breast RT (APBI), regional nodal irradiation (RNI), RT for ductal carcinoma in situ (DCIS), postmastectomy RT (PMRT), and tumor bed boost. RESULTS: Seventy radiation oncologists from 61 (out of 101; 60%) institutions participated in the survey. HypoFx RT was used by 62 respondents (89%), a significant increase from 36% in 2017. HypoFx RT is commonly administered at 40-42.5 Gy in 15-16 fractions. APBI was used by 12 respondents (17%), an increase from 5% in 2017. The use of RNI did not change significantly: ≥ pN2 (6%), ≥ pN1 (33%), and ≥ pN1 with pathological risk factors (61%). However, indications for internal mammary lymph node (IMN) irradiation have expanded. In particular, the rates of routine treatment of IMN (11% from 6% in 2017) and treatment in cases of ≥ pN2 (27% from 14% in 2017) have doubled; however, the rate of treatment for only IMN involvement, identified on imaging, has decreased from 47% in 2017 to 31%. For DCIS, the use of HypoFx RT increased from 25% in 2017 to 75%, and the rate of RT omissions after breast-conserving surgery (BCS) decreased from 48% in 2017 to 38%. The use of HypoFx RT for PMRT increased from 8% in 2017 to 36%. CONCLUSION: The adoption of HypoFx RT after BCS for invasive breast cancer and DCIS has increased significantly, whereas the use of HypoFx PMRT has increased moderately since 2017. However, further studies are required to determine the optimal use of RNI.

A Survey of Practice Patterns for Clinical Nodal Staging Prior to Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND: The importance of clinical staging in breast cancer has increased owing to the wide use of neoadjuvant systemic therapy (NST). This study aimed to investigate the current practice patterns regarding clinical nodal staging in breast cancer in real-world settings. MATERIALS AND METHODS: A web-based survey was administered to board-certified oncologists in Korea, including breast surgical, medical, and radiation oncologists, from January to April 2022. The survey included 19 general questions and 4 case-based questions. RESULTS: In total, 122 oncologists (45 radiation, 44 surgical, and 33 medical oncologists) completed the survey. Among them, 108 (88%) responded that clinical staging before NST was primarily performed by breast surgeons. All the respondents referred to imaging studies during nodal staging. Overall, 64 (52.5%) responders determined the stage strictly based on the radiology reports, whereas 58 (47.5%) made their own decision while noting radiology reports. Of those who made their own decisions, 88% referred to the number or size of the suspicious node. Of the 75 respondents involved in prescribing regimens for neoadjuvant chemotherapy, 58 (77.3%) responded that the reimbursement regulations in the selection of NST regimens affected nodal staging in clinical practice. In the case-based questions, high variability was observed among the clinicians in the same cases. CONCLUSIONS: Diverse assessments by specialists owing to the lack of a clear, harmonized staging system for the clinical nodal staging of breast cancer can lead to diverse practice patterns. Thus, practical, harmonized, and objective methods for clinical nodal staging and for the outcomes of post-NST response are warranted for appropriate treatment decisions and accurate outcome evaluation.

Comparison of initial and sequential salvage brain-directed treatment in patients with 1-4 vs. 5-10 brain metastases from breast cancer (KROG 16-12).

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

Evaluation of initial patient setup methods for breast cancer between surface-guided radiation therapy and laser alignment based on skin marking in the Halcyon system.

BACKGROUND: This study was conducted to evaluate the efficiency and accuracy of the daily patient setup for breast cancer patients by applying surface-guided radiation therapy (SGRT) using the Halcyon system instead of conventional laser alignment based on the skin marking method. METHODS AND MATERIALS: We retrospectively investigated 228 treatment fractions using two different initial patient setup methods. The accuracy of the residual rotational error of the SGRT system was evaluated by using an in-house breast phantom. The residual translational error was analyzed using the couch position difference in the vertical, longitudinal, and lateral directions between the reference computed tomography and daily kilo-voltage cone beam computed tomography acquired from the record and verification system. The residual rotational error (pitch, yaw, and roll) was also calculated using an auto rigid registration between the two images based on Velocity. The total setup time, which combined the initial setup time and imaging time, was analyzed to evaluate the efficiency of the daily patient setup for SGRT. RESULTS: The average residual rotational errors using the in-house fabricated breast phantom for pitch, roll, and yaw were 0.14°, 0.13°, and 0.29°, respectively. The average differences in the couch positions for laser alignment based on the skin marking method were 2.7 ± 1.6 mm, 2.0 ± 1.2 mm, and 2.1 ± 1.0 mm for the vertical, longitudinal, and lateral directions, respectively. For SGRT, the average differences in the couch positions were 1.9 ± 1.2 mm, 2.9 ± 2.1 mm, and 1.9 ± 0.7 mm for the vertical, longitudinal, and lateral directions, respectively. The rotational errors for pitch, yaw, and roll without the surface-guided radiation therapy approach were 0.32 ± 0.30°, 0.51 ± 0.24°, and 0.29 ± 0.22°, respectively. For SGRT, the rotational errors were 0.30 ± 0.22°, 0.51 ± 0.26°, and 0.19 ± 0.13°, respectively. The average total setup times considering both the initial setup time and imaging time were 314 s and 331 s, respectively, with and without SGRT. CONCLUSION: We demonstrated that using SGRT improves the accuracy and efficiency of initial patient setups in breast cancer patients using the Halcyon system, which has limitations in correcting the rotational offset.

Omission of axillary lymph node dissection in patients with ypN+ breast cancer after neoadjuvant chemotherapy: A retrospective multicenter study (KROG 21-06).

BACKGROUND: We evaluated the impact of omitting axillary lymph node dissection (ALND) on oncological outcomes in breast cancer patients with residual nodal disease after neoadjuvant chemotherapy (NAC). METHODS: The medical records of patients who underwent NAC followed by surgical resection and had residual nodal disease were retrospectively reviewed. In total, 1273 patients from 12 institutions were included; all underwent postoperative radiotherapy. Axillary surgery consisted of ALND in 1103 patients (86.6%) and sentinel lymph node biopsy (SLNBx) alone in 170 (13.4%). Univariate and multivariate analyses of disease-free survival (DFS) and overall survival (OS) were performed before and after propensity score matching (PSM). RESULTS: The median follow-up was 75.3 months (range, 2.5-182.7). Axillary recurrence rates were 4.8% in the ALND group (n = 53) and 4.7% in the SLNBx group (n = 8). Before PSM, univariate analysis indicated that the 5-year OS rate was inferior in the ALND group compared to the SLNBx group (86.6% vs. 93.3%, respectively; P = 0.002); multivariate analysis did not show a difference between groups (P = 0.325). After PSM, 258 and 136 patients were included in the ALND and SLNBx groups, respectively. There were no significant differences between the ALND and SLNBx groups in DFS (5-year rate, 75.8% vs. 76.9%, respectively; P = 0.406) or OS (5-year rate, 88.7% vs. 93.1%, respectively; P = 0.083). CONCLUSIONS: SLNBx alone did not compromise oncological outcomes in patients with residual nodal disease after NAC. The omission of ALND might be a possible option for axillary management in patients treated with NAC and postoperative radiotherapy.

Near-maximum rib dose is the most relevant risk factor for ipsilateral spontaneous rib fracture: a dosimetric analysis of breast cancer patients after radiotherapy.

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

Impact of Postmastectomy Radiation Therapy on Breast Cancer Patients According to Pathologic Nodal Status after Modern Neoadjuvant Chemotherapy.

PURPOSE: The utility of postmastectomy radiation therapy (PMRT) for breast cancer patients after neoadjuvant chemotherapy (NAC) is highly controversial. This study evaluated the impact of PMRT according to pathologic nodal status after modern NAC. Materials and Methods: We retrospectively reviewed 682 patients with clinical stage II-III breast cancer who underwent NAC and mastectomy from 2013 to 2017. In total, 596 patients (87.4%) received PMRT, and 86 (12.6%) did not. We investigated the relationships among locoregional recurrence-free survival (LRRFS), disease-free survival (DFS), overall survival (OS), and various prognostic factors. Subgroup analyses were also performed to identify patients who may benefit from PMRT. RESULTS: The median follow-up duration was 67 months. In ypN+ patients (n=368, 51.2%), PMRT showed significant benefits in terms of LRRFS, DFS, and OS (all p < 0.001). In multivariate analyses, histologic grade (HG) III (p=0.002), lymphovascular invasion (LVI) (p=0.045), and ypN2-3 (p=0.02) were significant risk factors for poor LRRFS. In ypN1 patients with more than two prognostic factors among luminal/human epidermal growth factor receptor-2-negative subtype, HG I-II, and absence of LVI, PMRT had no significant effect on LRRFS (p=0.18). In ypN0 patients (n=351, 48.8%), PMRT was not significantly associated with LRRFS, DFS, or OS. However, PMRT showed better LRRFS in triple-negative breast cancer (TNBC) patients (p=0.03). CONCLUSION: PMRT had a major impact on treatment outcomes in patients with residual lymph nodes following NAC and mastectomy. Among ypN0 patients, PMRT may be beneficial only for those with TNBC.

Protocol for the postoperative radiotherapy in N1 breast cancer patients (PORT-N1) trial, a prospective multicenter, randomized, controlled, non-inferiority trial of patients receiving breast-conserving surgery or mastectomy.

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

Prediction of breast cancer-related lymphedema risk after postoperative radiotherapy via multivariable logistic regression analysis.

Purpose: We identified novel clinical and dosimetric prognostic factors affecting breast cancer-related lymphedema after postoperative radiotherapy (RT) and developed a multivariable logistic regression model to predict lymphedema in these patients. Methods and materials: In total, 580 patients with unilateral breast cancer were retrospectively reviewed. All patients underwent breast surgery and postoperative RT with or without systemic treatment in 2015. Among the 580 patients, 532 with available RT plan data were randomly divided into training (n=372) and test (n=160) cohorts at a 7:3 ratio to generate and validate the lymphedema prediction models, respectively. An area under the curve (AUC) value was estimated to compare models. Results: The median follow-up duration was 5.4 years. In total, 104 (17.9%) patients experienced lymphedema with a cumulative incidence as follows: 1 year, 10.5%; 3 years, 16.4%; and 5 years, 17.6%. Multivariate analysis showed that body mass index ≥25 kg/m2 (hazard ratio [HR] 1.845), dissected lymph nodes ≥7 (HR 1.789), and taxane-base chemotherapy (HR 4.200) were significantly associated with increased lymphedema risk. Conversely, receipt of RT at least 1 month after surgery reduced the risk of lymphedema (HR 0.638). A multivariable logistic regression model using the above factors, as well as the minimum dose of axillary level I and supraclavicular lymph node, was created with an AUC of 0.761 and 0.794 in the training and test cohorts, respectively. Conclusions: Our study demonstrated that a shorter interval from surgery to RT and other established clinical factors were associated with increased lymphedema risk. By combining these factors with two dosimetric parameters, we propose a multivariable logistic regression model for breast cancer-related lymphedema prediction after RT.

Intensity Modulated Radiotherapy and Volumetric Modulated Arc Therapy in the Treatment of Breast Cancer: An Updated Review.

Radiation therapy (RT) plays a critical role in breast cancer treatment. In the modern technological era, innovations and progress in breast RT and delivery techniques have greatly improved the clinical outcomes. Intensity-modulated RT (IMRT) is a modern RT technology that permits the modulation of RT beams, ensuring a more uniform dose distribution through the target tissue and better avoidance of underlying critical structures. Recently, several studies have been published on breast IMRT. However, the interpretation of these results can be challenging because of the wide diversity of patients and treatment. The purpose of this study was to review these studies, focusing on the impact of IMRT on reducing toxicity and increasing convenience, as well as addressing concerns regarding breast IMRT.

No axillary surgical treatment for lymph node-negative patients after ultra-sonography [NAUTILUS]: protocol of a prospective randomized clinical trial.

BACKGROUND: Following sentinel lymph node biopsy (SLNB), the axillary recurrence rate is very low although SLNB has a false-negative rate of 5-10%. In the ACOSOG Z0011 trial, non-sentinel positive-lymph nodes were found in more than 20% of the axillary dissection group; the SLNB only group did not have a higher axillary recurrence rate. These findings raised questions about the direct therapeutic effect of the SLNB. SLNB has post-surgical complications including lymphedema. Considering advances in imaging modalities and adjuvant therapies, the role of SLNB in early breast cancer needs to be re-evaluated. METHODS: The NAUTILUS trial is a prospective multicenter randomized controlled trial involving clinical stage T1-2 and N0 breast cancer patients receiving breast-conserving surgery. Axillary ultrasound is mandatory before surgery with predefined imaging criteria for inclusion. Ultrasound-guided core needle biopsy or needle aspiration of a suspicious node is allowed. Patients will be randomized (1:1) into the no-SLNB (test) and SLNB (control) groups. A total of 1734 patients are needed, considering a 5% non-inferiority margin, 5% significance level, 80% statistical power, and 10% dropout rate. All patients in the two groups will receive ipsilateral whole-breast radiation according to a predefined protocol. The primary endpoint of this trial is the 5-year invasive disease-free survival. The secondary endpoints are overall survival, distant metastasis-free survival, axillary recurrence rate, and quality of life of the patients. DISCUSSION: This trial will provide important evidence on the oncological safety of the omission of SLNB for early breast cancer patients undergoing breast-conserving surgery and receiving whole-breast radiation, especially when the axillary lymph node is not suspicious during preoperative axillary ultrasound. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04303715 . Registered on March 11, 2020.

Postmastectomy Radiation Therapy in Patients With Minimally Involved Lymph Nodes: A Review of the Current Data and Future Directions.

Radiation therapy for patients with pN1mi or pN1 disease breast cancer undergoing mastectomy has been debated for a long time. Even in low metastatic burden in sentinel node biopsy, occult non-sentinel axillary nodal involvement can exist. Radiotherapy can sterilize axillary metastatic burden and seems to contribute a very low local recurrence rate in mastectomy patients with minimally involved lymph nodes. However, it should be considered that systemic therapy is evolving and the local recurrence difference between radiotherapy and no radiotherapy is relatively small. Regarding postmastectomy radiotherapy in patients pN1mi or pN1 cancer, published prospective clinical trial results should be considered; however, there are no such relevant results of clinical trials yet. Consideration of postmastectomy radiation therapy in pN1mi or pN1 patients should be based on identifying the high-risk group in terms of recurrence, stage, or tumor biology. When radiotherapy is determined, radiation oncologists should attempt individualized treatment approaches, such as irradiation field, and consider specific settings, such as neoadjuvant therapy. In this review, the role of radiotherapy in mastectomy patients with minimally involved lymph nodes and the relevant considerations are discussed.