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Purpose Questions remain about whether moderately hypofractionated whole-breast irradiation is appropriate for patients with triple-negative breast cancer. Methods and Materials Using the prospective database of a multicenter, collaborative quality improvement consortium, we identified patients with node-negative, triple-negative breast cancer who received whole-breast irradiation with either moderate hypofractionation or conventional fractionation. Using inverse probability of treatment weighting (IPTW), we compared outcomes using the Kaplan-Meier product-limit estimation method with Cox regression models estimating the hazard ratio for time-to-event endpoints between groups. Results The sample included 538 patients treated at 18 centers in 1 state in the United States, of whom 307 received conventionally fractionated whole-breast irradiation and 231 received moderately hypofractionated whole-breast irradiation. The median follow-up time was 5.0 years (95% confidence interval [CI], 4.77-5.15 years). The 5-year IPTW estimates for freedom from local recurrence were 93.6% (95% CI, 87.8%-96.7%) in the moderate hypofractionation group and 94.4% (95% CI, 90.3%-96.8%) in the conventional fractionation group. The hazard ratio was 1.05 (95% CI, 0.51-2.17; P = .89). The 5-year IPTW estimates for recurrence-free survival were 87.8% (95% CI, 81.0%-92.4%) in the moderate hypofractionation group and 88.4% (95% CI 83.2%-92.1%) in the conventional fractionation group. The hazard ratio was 1.02 (95% CI, 0.62-1.67; P = .95). The 5-year IPTW estimates for overall survival were 96.6% (95% CI, 92.0%-98.5%) in the moderate hypofractionation group and 93.4% (95% CI, 88.7%-96.1%) in the conventional fractionation group. The hazard ratio was 0.65 (95% CI, 0.30-1.42; P = .28). Conclusions Analysis of outcomes in this large observational cohort of patients with triple-negative, node-negative breast cancer treated with whole-breast irradiation revealed no differences by dose fractionation. This adds evidence to support the use of moderate hypofractionation in patients with triple-negative disease.

Radiation therapy (RT) is an essential component in the management of breast cancer. Following breast-conserving surgery (BCS), adjuvant RT is the standard of care for most patients. Traditionally, RT was delivered with standard whole breast irradiation (WBI) over 5-7 weeks following BCS. However, WBI regimens have evolved; hypofractionated WBI now represents the standard approach, reducing the duration of treatment to 3-4 weeks. Over the past year, five-fraction WBI regimens have also emerged as standard of care for some patients based on data from the FAST and FAST-Forward trials. An alternative to WBI that is also available for patients with early-stage breast cancer following BCS is partial breast irradiation, which can reduce the duration of treatment and the volume of breast tissue irradiated. Outcomes from multiple randomized trials with over a 10-year follow-up have demonstrated the safety and efficacy of partial breast irradiation approaches. Single-fraction intraoperative RT has also been evaluated in two prospective trials although the outcomes available, as well as current guidelines, do not support its utilization outside of prospective studies. For patients requiring RT to the regional lymph nodes, data have demonstrated the safety of hypofractionated approaches for those undergoing BCS or mastectomy without reconstruction. Future directions for early-stage breast cancer radiotherapy include the study of even shorter regimens and studies evaluating the omission of RT versus omission of endocrine therapy for favorable-risk patients. Furthermore, studies are also underway evaluating shorter courses of radiation in patients undergoing breast reconstruction and the use of tumor genomics to identify appropriate patients for omission of radiation with limited nodal involvement.

Background The role of radiation therapy (RT) following breast-conserving surgery (BCS) in ductal carcinoma in situ (DCIS) remains controversial. Trials have not identified a low-risk cohort, based on clinicopathologic features, who do not benefit from RT. A biosignature (DCISionRT®) that evaluates recurrence risk has been developed and validated. We evaluated the impact of DCISionRT on clinicians’ recommendations for adjuvant RT. Methods The PREDICT study is a prospective, multi-institutional, observational registry in which patients underwent DCISionRT testing. The primary endpoint was to identify the percentage of patients where testing led to a change in RT recommendations. Results Overall, 539 women were included in this study. Pre DCISionRT testing, RT was recommended to 69% of patients; however, post-testing, a change in the RT recommendation was made for 42% of patients compared with the pre-testing recommendation; the percentage of women who were recommended RT decreased by 20%. For women initially recommended not to receive an RT pre-test, 35% had their recommendation changed to add RT following testing, while post-test, 46% of patients had their recommendation changed to omit RT after an initial recommendation for RT. When considered in conjunction with other clinicopathologic factors, the elevated DCISionRT score risk group (DS > 3) had the strongest association with an RT recommendation (odds ratio 43.4) compared with age, grade, size, margin status, and other factors. Conclusions DCISionRT provided information that significantly changed the recommendations to add or omit RT. Compared with traditional clinicopathologic features used to determine recommendations for or against RT, the factor most strongly associated with RT recommendations was the DCISionRT result, with other factors of importance being patient preference, tumor size, and grade.

BACKGROUND: Current national guidelines encourage consideration for treating the at-risk regional nodes (axillary, supraclavicular, and/or internal mammary) with directed regional nodal irradiation (RNI) during post-lumpectomy radiotherapy for high risk N0 (node negative) and N1 (1-3 nodes positive) breast cancer patients. This recommendation is based on the results of several randomized trials published over the last decade. Evidence regarding translation of these trials into clinical practice in the United States has been limited to date. In this study, we sought to characterize the temporal changes in and clinical factors associated with the utilization of RNI during post-lumpectomy radiotherapy for N0-N1 breast cancer across a contemporary, statewide consortium of radiation oncology practices. METHODS: Within a statewide radiation oncology quality consortium, 12,170 breast cancer patients were consecutively enrolled between 1/1/2013 and 10/31/2019 in both academic (teaching) and community (non-teaching) facilities. Data on receptor status, adjuvant systemic therapy, age, TNM stage, extent of axillary surgery, race, body mass index (BMI), type of treating facility, and year completing radiotherapy (RT) were collected. Eligibility for the present analysis was limited to patients with N0 and N1 disease not receiving neoadjuvant systemic therapy and receiving adjuvant radiotherapy after lumpectomy for non-metastatic breast cancer. Multiple variable logistic regression models were separately fit to explain the use of directed RNI (to the axilla, supraclavicular region, and/or internal mammary region) for the N0 and N1 populations separately and described using odds ratios (OR), with significant ORs (p RESULTS: A total of 8,468 patients from 29 treating facilities met the inclusion criteria: 6,929 (81.8%) with N0 and 1,539 (18.2%) N1 disease. RNI was performed in addition to whole breast radiation in 95 (1.4%) and 908 (59%) patients in the N0 and N1 cohorts respectively. For the N0 cohort, significant correlates of RNI on multivariable analysis (MVA) were receipt of adjuvant chemotherapy (OR 2.7), higher T-stage (OR 1.9 for T2 vs T1 and 27.3 for T3/T4 vs T1), axillary surgery [compared to sentinel node biopsy (SLN) alone : no axillary surgery (OR 14.5), axillary lymph node dissection (ALND) with 10+ nodes removed (OR 15.1) ALND after SLN (OR 2.7)], and underweight BMI (OR 4.9 compared to overweight, which was the reference as the largest BMI category). For the N1 cohort, MVA suggested adjuvant chemotherapy (OR 1.8) and larger tumors (OR 1.6 [T2 vs T1]) were significantly associated with use of RNI. The year completing RT was also significantly associated with RNI use, with 22% and 15% increases per year from 2013 to 2019 in the N0 and N1 cohorts, respectively. Lastly, receiving treatment in an academic facility compared to a community facility was significantly associated with receipt of RNI in both the N0 (OR 1.8) and N1 (OR 2.2) cohorts. CONCLUSION: In this large cohort, selective use of RNI added to post-lumpectomy whole breast radiotherapy is estimated to have increased over time, suggesting growing implementation of recent trial data and current clinical practice guidelines. Patient, treatment, and tumor characteristics appear to factor into the decision to treat with RNI, but differences in use between academic and community practices suggest opportunities for improving the consistency of care across care delivery settings. Ongoing trials seeking to identify subgroups of N1 patients in whom RNI can safely be omitted may be especially important to inform decisions, given the almost even split (59% receiving, 41% not) in practice observed in this large American cohort. Citation Format: Derek Bergsma, Kent Griffith, Reshma Jagsi, Michael Dominello, Thomas Boike, Joshua Dilworth, Amit Bhatt, Frank Vicini, Maggie Grubb, Jean Moran, James Hayman, Lori Pierce, on behalf of MROQC, the Michigan Radiation Oncology Quality Consortium. Contemporary practice patterns for the use of regional nodal irradiation during post-lumpectomy radiotherapy for patients with N0/N1 breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD4-07.

BACKGROUND: Evaluating whether physicians (MDs) accurately detect symptoms in patients (pts) is important because recognition of symptoms facilitates supportive care and because clinical trials often rely on MD assessments using the Common Toxicity Criteria for Adverse Events (CTCAE). METHODS: Breast cancer pts who received radiotherapy (RT) after lumpectomy at 29 practices were enrolled in a quality initiative, MROQC. Of 13,725 pts who completed RT between 1/1/2012 and 3/31/2020, 9,941 completed at least one pt-reported outcomes (PRO) questionnaire during RT. Where MD CTCAE assessments were available within 3 days of PRO evaluation, pt and MD ratings of 4 symptoms were compared. Pts reported breast pain via an approved modification of the Brief Pain Inventory, asking for ratings in the last 24 hours of pain at its worst, least, average, and “right now.” MDs were deemed to under-recognize pain when pts reported moderate pain (score 4-6) but MDs graded pain as 0 (absent) on the CTCAE, or when pts reported severe pain (score 7-10) but MDs’ CTCAE grade was ≤1. Bother from pruritis and edema were measured by modified scaled measures adapted from the Skindex. MDs were deemed to under-recognize pruritus and edema if they graded these as absent (grade 0) when pts reported bother often or all of the time from itching or swelling, respectively. MDs were deemed to under-recognize fatigue if they graded fatigue as absent (grade 0) when pts reported having significant fatigue most of the time or always.We describe the proportion of pts for whom under-recognition of at least 1 of these 4 symptoms occurred at least once during the treatment course and use multivariable logistic regression to evaluate predictors of this under-recognition, hypothesizing that it would be more common in racial minorities. RESULTS: 3,434/9,940 pts (34.5%) reported substantial breast pain, 3,039/9,923 (30.6%) frequent bother from pruritus, 2,363/9,906 (23.9%) frequent bother from edema, and 2,209/8,860 (24.9%) severe fatigue. We could evaluate under-recognition in 9,868 pts, with 37,593 independent paired observations of pt and MD reports (35,797 on the same date and 1,796 within 3 days). Under-recognition existed in 2,094/6,781 (30.9%) observations of pt-reported moderate/severe pain, 748/2,039 (36.7%) of pt-reported frequent pruritis, 2,309/4,492 (51.4%) of pt-reported frequent edema, and 390/2,079 (18.8%) of pt-reported severe fatigue. Under-recognition of at least 1 of these 4 symptoms occurred at least once during the pt’s treatment course for 2,933/5,510 (53.2%) of the pts who reported at least 1 substantial symptom during RT.Factors independently associated with under-recognition were (Table): younger age (OR=1.4 and 1.2 for CONCLUSIONS: PRO collection appears essential for trials because relying on the CTCAE to detect adverse events may miss important symptoms. Moreover, since MDs systematically miss substantial symptoms in certain patients, including pts who are younger or of black or other race, improving symptom detection may be a targetable mechanism to reduce disparities in RT experiences and outcomes. Multivariable model of symptom under-recognitionOR95% CIpAge--0.001 Citation Format: Reshma Jagsi, Kent A. Griffith, Frank Vicini, Thomas Boike, Michael Dominello, Gregory Gustafson, James A. Hayman, Jean M. Moran, Jeffrey Radawski, Eleanor Walker, Lori J. Pierce, on behalf of MROQC, the Michigan Radiation Oncology Quality Consortium. Identifying patients whose symptoms are under-recognized during breast radiotherapy: Comparison of patient and physician reports of toxicity in a multicenter cohort [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-07.

BACKGROUND: When considering health-related, quality-of-life and monetary costs associated with post-surgical treatments for women diagnosed with Ductal Carcinoma In Situ (DCIS), there remains a need for prognostic and predictive tools to help design individual treatment planning. DCISionRT (PreludeDx, Laguna Hills, CA) is a validated biologic signature to assess the 10-year event risk for DCIS patients managed with breast conserving surgery (BCS). The 10-year risks are provided separately for patients treated with and without adjuvant radiation therapy (RT) after BCS. The study was designed to measure the change in adjuvant RT recommendation. This is a planned interim analysis of the study, which will eventually comprise up to 2,500 patients and 100 sites. METHODS: The registry includes females over the age of 25 who are candidates for breast conserving surgery and eligible for RT. Survey forms are completed pre- and post-DCISionRT test to capture treatment recommendations and patient preferences. This interim analysis was performed to assess changes in RT recommendation for patients treated with BCS in different clinicopathologic subgroups. Specifically, ‘good risk’ profiles were based on the RTOG 9804 and ECOG 5194 study designs. RTOG 9804 like criteria was screening detected tumors with nuclear grade of 1 or 2, size of ≤ 2.5 cm, and clear (≥ 2 mm) surgical margins. ECOG 5194 like criteria was tumors with nuclear grade of 1 or 2, size of ≤ 2.5 cm, and clear surgical margins, or nuclear grade of 3, size of ≤ 1 cm, and clear surgical margins. Statistics were provided as percentages and counts, and McNemar’s test was used to assess change in RT with a p-value of RESULTS: There were 513 patients from 32 sites with testing completed after treatment with BCS. Of these patients, 16% were ≤ 50 years of age, 60% were ≥ 60 years of age, and 26% were ≥ 70 years of age. The DCIS tumor nuclear grade was high in 32% of patients, and the size of the tumor was ≤ 1 cm for 68% of patients. There were 49% of patients who met RTOG 9804 like criteria, 51% who met the ECOG 5194 (grade 1 or 2) criteria, and 45% of patients who met the ECOG 5194 (grade 3) criteria. RT was recommended to 52% and 53% patients for RTOG 9804/ECOG 5194 (grade 1 or 2) criteria pre-testing, and 42% post-testing. For ECOG 5194 (grade 3) like criteria, 64% of patients were recommended RT pre-test, and 40% were recommended RT post-test. In all criteria groups, for patients whom were initially recommended RT pre-test, 51% to 54% were not recommended RT post-test, while patients initially not recommended RT pre-test, 25% to 37% were recommended RT post-test. Overall, the post-test RT recommendation was significantly changed from between 42% and 46% for patients with ‘good-risk’ clinicopathologic criteria. CONCLUSIONS: The PREDICT study interim analysis demonstrates a significant absolute overall change post DCISionRT testing for RT recommendation in patients with ‘good-risk’ clinicopathology. RT recommendations were changed post-test for 42% to 46% of patients meeting RTOG 9804/ECOG 5194 like criteria. Integration of DCISionRT testing had a significant impact on the RT recommendations aimed at reducing overtreatment and minimizing undertreatment. Table 1. Pre-Post DCISionRT Impact by ‘good-risk’ criteria.n% RTPre-testYes% RTPost-test Yes% RTPre-Yes, Post-No% RTPre-No, Post-Yes% Total Decision Change95% CIp-valueRTOG 9804 criteriaGrade 1 or 2, Size ≤ 2.5 cm, screen detected, wide margins2525242543746%40 - 52%1.2E-02ECOG E5194 criteriaGrade 1 and 2, Size ≤ 2.5 cm, wide margins2625342533645%39 - 51%0.010Grade 3, Size ≤ 1 cm, wide margins2316440512542%36 - 48%2.4E-08 Citation Format: Chirag Shah, Frank Vicini, Steven C Shivers, Pat W Whitworth, Rakesh Patel, Charles E Cox, Troy Bremer. Clinical utility of a biologic signature to assess DCIS recurrence risk in patients meeting ‘good-risk’ criteria (RTOG 9804, ECOG 5194): Interim analysis of the DCISionRT PREDICT study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-17.

Purpose Breast cancer-related lymphedema (BCRL) represents a significant concern for patients following breast cancer treatment, and assessment for BCRL represents a key component of survivorship efforts. Growing data has demonstrated the benefits of early detection and treatment of BCRL. Traditional diagnostic modalities are less able to detect reversible subclinical BCRL while newer techniques such as bioimpedance spectroscopy (BIS) have shown the ability to detect subclinical BCRL, allowing for early intervention and low rates of chronic BCRL with level I evidence. We present updated clinical practice guidelines for BIS utilization to assess for BCRL. Methods and Results Review of the literature identified a randomized controlled trial and other published data which form the basis for the recommendations made. The final results of the PREVENT trial, with 3-year follow-up, demonstrated an absolute reduction of 11.3% and relative reduction of 59% in chronic BCRL (through utilization of compression garment therapy) with BIS as compared to tape measurement. This is in keeping with real-world data demonstrating the effectiveness of BIS in a prospective surveillance model. For optimal outcomes patients should receive an initial pre-treatment measurement and subsequently be followed at a minimum quarterly for first 3 years then biannually for years 4–5, then annually as appropriate, consistent with previous guidelines; the target for intervention has been changed from a change in L-Dex of 10 to 6.5. The lack of pre-operative measure does not preclude inclusion in the prospective surveillance model of care. Conclusion The updated clinical practice guidelines present a standardized approach for a prospective model of care using BIS for BCRL assessment and supported by evidence from a randomized controlled trial as well as real-world data.

PURPOSE Understanding acute toxicities after whole-breast radiotherapy is important to inform patients, guide treatment decisions, and target supportive care. We evaluated patient-reported outcomes prospectively collected from a cohort of patients with breast cancer. METHODS We describe the maximal toxicity reported by 8,711 patients treated between 2012 and 2019 at 27 practices. Multivariable models identified characteristics associated with (1) breast pain, (2) bother from itching, stinging/burning, swelling, or hurting of the treated breast, and (3) fatigue within 7 days of completing whole-breast radiotherapy. RESULTS Moderate or severe breast pain was reported by 3,233 (37.1%): 1,282 (28.9%) of those receiving hypofractionation and 1,951 (45.7%) of those receiving conventional fractionation. Frequent bother from at least one breast symptom was reported by 4,424 (50.8%): 1,833 (41.3%) after hypofractionation and 2,591 (60.7%) after conventional fractionation. Severe fatigue was reported by 2,008 (23.1%): 843 (19.0%) after hypofractionation and 1,165 (27.3%) after conventional fractionation. Among patients receiving hypofractionated radiotherapy, younger age ( P < .001), higher body mass index (BMI; P < .001), Black ( P < .001) or other race ( P = .002), smoking status ( P < .001), larger breast volume ( P = .002), lack of chemotherapy receipt ( P = .004), receipt of boost treatment ( P < .001), and treatment at a nonteaching center predicted breast pain. Among patients receiving conventionally fractionated radiotherapy, younger age ( P < .001), higher BMI ( P = .003), Black ( P < .001) or other race ( P = .002), diabetes ( P = .001), smoking status ( P < .001), and larger breast volume ( P < .001) predicted breast pain. CONCLUSION In this large observational data set, substantial differences existed according to radiotherapy dose fractionation. Race-related differences in pain existed despite controlling for multiple other factors; additional research is needed to understand what drives these differences to target potentially modifiable factors. Intensifying supportive care may be appropriate for subgroups identified as being vulnerable to greater toxicity.

The American Brachytherapy Society brachytherapy schools have been pivotal in teaching and evolving the art of brachytherapy over the past decades. Founded in 1995, the schools have consistently provided content for the major disease sites including gynecologic, prostate, and breast with ocular, vascular, head and neck, pediatric, intraluminal, systemic, and intraoperative approaches more selectively addressed. In addition, Physics schools, either coupled with clinical schools or as stand-alone venues, have provided an essential educational component for practicing physicists, a pivotal part of the brachytherapy team. Celebrating 25 years in existence, this historical overview of the American Brachytherapy Society brachytherapy schools is a tribute to the many teachers who have shared their expertise, to the many students who have been enthusiastic and interactive participants, and the staff who have made it all possible, with the reward of perpetuating the important and timely art of brachytherapy.

Purpose: An interim analysis of 508 patients who completed 12 months of prospective surveillance in the lymphedema PREVENT study found a significant difference in the time to preventive intervention trigger between those measured with Bioelectrical Impedance Spectroscopy (BIS) (9.5 months) vs. Tape Measure (TM) (2.8 months). However, questions emerged as to the reason for the difference and associated factors. Therefore, a study was performed to determine the factors that influenced the time to intervention trigger in patients randomized to either BIS or TM during the first 2 years post-operatively. Methods: Post-randomization to BIS or TM groups patients were assessed with the assigned measurement method at intervals of at least 3, 6, 12, 18, and 24 months post-operatively. A lymphedema prevention intervention consisting of wearing a compression sleeve and a gauntlet for 12 hours a day for 28 days was triggered when subclinical lymphedema was indicated. A change from baseline measures in the BIS group ≥ 6.5 L-DEX units and in TM ≥ 5% but Citation Format: Sheila Hedden Ridner, Mary S Dietrich, Chirag Shah, Frank Vicini. Factors associated with triggering events on the PREVENT trial at 2 years post-operatively [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-15.

There is an unmet need to identify women diagnosed with ductal carcinoma in situ (DCIS) with a low risk of in-breast recurrence (IBR) after breast conserving surgery (BCS), which could omit radiation therapy (RT), and also to identify those with elevated IBR risk remaining after BCS plus RT. We evaluated a novel biosignature for a residual risk subtype (RRt) to help identify patients with elevated IBR risk after BCS plus RT.Women with DCIS treated with BCS with or without RT at centers in the US, Australia, and Sweden (n = 926) were evaluated. Patients were classified into 3 biosignature risk groups using the decision score (DS) and the RRt category: (1) Low Risk (DS ≤2.8 without RRt), (2) Elevated Risk (DS2.8 without RRt), and (3) Residual Risk (DS2.8 with RRt). Total and invasive IBR rates were assessed by risk group and treatment.In patients at low risk, there was no significant difference in IBR rates with or without RT (total, P = .8; invasive IBR, P = .7), and there were low overall 10-year rates (total, 5.1%; invasive, 2.7%). In patients with elevated risk, IBR rates were decreased with RT (total: hazard ratio [HR], 0.25; P.001; invasive: HR, 0.28; P = .005); 10-year rates were 20.6% versus 4.9% (total) and 10.9% versus 3.1% (invasive). In patients with residual risk, although IBR rates decreased with RT after BCS (total: HR, 0.21; P.001; invasive: HR, 0.29; P = .028), IBR rates remained significantly higher after RT compared with patients with elevated risk (HR, 2.5; 95% CI, 1.2-5.4; P = .018), with 10-year rates of 42.1% versus 14.7% (total) and 18.3% versus 6.5% (invasive).The novel biosignature identified patients with 3 distinct risk profiles: Low Risk patients with a low recurrence risk with or without adjuvant RT, Elevated Risk patients with excellent outcomes after BCS plus RT, and Residual Risk patients with an elevated recurrence risk remaining after BCS plus RT, warranting potential intensified or alternative treatment approaches.

Background: NCCN treatment guidelines support de-escalation of radiotherapy (RT) for “low risk” patients with ductal carcinoma in situ (DCIS) treated with breast conserving surgery (BCS) for which improved specificity in identifying patients with low in-breast recurrence (IBR) rates who are unlikely to benefit from RT is needed. “low risk” has been defined as the absence of “high risk” clinicopathological (CP) factors, which include younger age (2.8 without RRt) and Residual Risk groups (DS>2.8 with RRt), where 10-yr total IBR rates were evaluated using Cox Proportional Hazards and Kaplan Meier analysis by treatment, biosignature Risk group, and CP criteria. Results: The biosignature classified 37% of women treated with BCS as Low Risk (n=338) and 63% (n=588) were classified into the combined Elevated/Residual Risk group. Among patients who did not receive RT, those in the Elevated/Residual Risk group had higher IBR rates (p Citation Format: Rachel Rabinovitch, Frank A. Vicini, Chirag Shah, Julie Margenthaler, Brian Czerniecki, Pat Whitworth, Sheila Weinmann, Michael C. Leo, Fredrik Wärnberg, G. Bruce Mann, Steven C. Shivers, David Dabbs, Karuna Mittal, Troy Bremer. Guiding de-escalation of treatment for patients with DCIS using a predictive 7-gene biosignature: Identification of a clinically low-risk patient group [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B016.

Following breast conserving surgery, the standard of care has been to deliver adjuvant radiation therapy directed to the whole breast (WBI) over a period of 3-7 weeks. Over the past decade, increasing data have supported the concept that treatment to the whole breast may not be required in selected patients, allowing for the emergence of partial breast irradiation (PBI). Multiple randomized trials with 5-10 years of follow-up have been published documenting the safety and efficacy associated with PBI using multiple techniques. Questions that remain to be answered include (a) what is the optimal PBI technique for each clinical scenario, (b) are there additional patients that can be effectively managed with PBI approaches, and (c) are there different techniques/dose schedules that allow for further reduction in treatment duration and/or toxicities? Partial breast irradiation represents a standard approach for appropriately selected patients. PBI provides comparable clinical outcomes to WBI while allowing for a reduction in the duration treatment and the potential for reduced toxicities. Future studies may also help to better define which patients require no radiation, PBI, hypofractionated WBI or conventional WBI, based upon patient, clinical, pathologic features as well as potentially using tumor genetics.

Objective: Elderly patients with low-risk hormone-positive breast cancer are at risk of over treatment. Avoidance of radiation therapy (RT) in favor of endocrine therapy alone was first heralded as the optimal conservative strategy due to logistical simplicity, low acute sequelae and a reduction of contralateral cancers not seen with RT. However, long-term use of aromatase inhibitors (AI) is not without costs and morbidity, often leading to low compliance and notable late effects. We therefore performed a cost-effectiveness analysis to compare the outcomes and costs between AI for five years without RT versus hypofractionated RT alone without endocrine therapy. Materials and Methods: Using data from available phase III trials and meta-analyses, we constructed a patient-level microsimulation Markov decision model to replicate the comparative outcomes between the strategies above from the societal perspective among 200,000 simulated patients. Five years of anastrozole was compared to a 15-fraction hypofractionated whole breast RT course without boost in a cohort of patients with low-risk disease as defined by CALGB 9343 entry criteria. Noncompliance with AI was modeled from recent population-based data. Relative effectiveness on ipsilateral breast tumor recurrence and contralateral breast cancers were based off the NSABP B-21 trial, adjusted to match the modern outcomes demonstrated in CALGB 9343 and PRIME II with further adjustment for AI over tamoxifen (ATAC, EBCTCG meta-analysis). Indirect costs of travel were accounted for, as were the costs of common and serious side-effects from RT (dermatitis, fibrosis, second malignancy, heart disease) and AI (arthralgia, hot flashes, osteopenia, fracture, thrombosis). A 1-year cycle time and lifetime horizon were used, with all costs adjusted to 2018 US dollars and extracted primarily from Medicare reimbursement data. The primary measure of efficacy was the quality-adjusted life-year (QALY) with age-adjusted utilities extracted from the literature. Half-cycle correction and a 3% discount rate were applied. Probabilistic sensitivity analysis was used to vary all parameters simultaneously. Results: On average, RT was approximately $3,981 more expensive than endocrine therapy over the lifetime horizon. Under a number of assumptions, RT appeared similar in long-term effectiveness to AI therapy, with a difference of less than 0.03 quality-adjusted life years. Given the low value of the denominator in the incremental cost-effectiveness ratio (ICER), RT did not meet the formally defined $100,000/QALY threshold. On one-way sensitivity analysis, the ICER was particularly sensitive to the incidence and impact of salvage strategies for recurrence, treatment of contralateral breast cancers, cardiac events and fracture rates. Conclusions: Modeling with the available evidence suggests it is likely that quality-of-life after RT-alone is nearly identical to an AI-alone strategy but associated with a small increase in cost. These results suggest select patients at risk of noncompliance can safely be treated with RT-alone rather than AI alone. Given the relative pros and cons of each strategy, RT-alone should be considered for select elderly low-risk breast patients. Citation Format: Ward MC, Vicini F, Chadha M, Pierce L, Recht A, Hayman J, Thaker N, Khan A, Keisch M, Shah C. Evaluating the cost of endocrine therapy vs. radiation therapy alone for low risk hormone positive early stage breast cancer in elderly patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-15-02.

Purpose/Objective(s) There is an unmet need to identify women diagnosed with DCIS who have a low recurrence risk and could omit radiotherapy (RT) after breast conserving surgery (BCS), or an elevated recurrence risk after treatment with BCS plus RT. Materials/Methods Pathology, clinical data, and FFPE tissue samples were evaluable for 485 women treated for DCIS with BCS with negative margins, with or without whole breast RT, at centers in Sweden, US and Australia. A subset with large tumor size (> 2.5 cm) &/or nuclear grade III DCIS was assessed (n = 250). A validated biosignature (Prelude, Laguna Hills CA) and a novel response subtype biosignature to RT after BCS were determined using protein biomarkers (p16/INK4A, Ki-67, COX-2, PgR, HER2, FOXA1, SIAH2) assayed on FFPE tissue. The two biosignatures classified women into three risk groups: Low risk, Elevated risk with a good response subtype (Rst) and Elevated risk with a poor Rst to RT after BCS. Ipsilateral breast tumor recurrence (IBTR) included DCIS or Invasive Breast Cancer (IBC) that was local, regional, or metastatic. Hazard ratios and 10-year risks were calculated using Cox proportional hazards and Kaplan-Meier analyses. Results Of 250 women with nuclear grade III DCIS and/or size > 2.5 cm, biosignatures classified 72% (n = 179) of patients into an Elevated risk group consisting of those with a good (n = 122) or a poor (n = 57) response subtype (Rst) to RT after BCS. The remaining 28% of women were classified into a low-risk group (n = 71). In the low-risk group (n = 71), women treated without RT had good 10-year outcomes with no (0%) 10-year IBC events, and derived no significant RT benefit (1%) in 10-year IBTR rates (IBTR P = 0.81). Of all women treated without RT (n = 102), those in the elevated risk group (good and poor Rst combined, n = 61) had significantly worse 10-year IBTR/IBC rates (31%/17%) than those in the low-risk group, (IBTR HR = 12, P = 0.01). Women treated with RT in the elevated risk group with a good Rst (n = 77) had significantly reduced 10-year IBTR/IBC rates of 5%/3%. However, no significant benefit to RT was noted for women within the elevated risk group with a poor Rst (n = 41) who had 10-year IBTR/IBC rates of 25%/20%. Of all women treated with RT in the elevated risk group (n = 118), those with a poor Rst had significantly worse outcomes than those with a good Rst (IBTR HR = 4.1, P = 0.035, IBC HR = 8, P = 0.053). Conclusion In women with nuclear grade III DCIS &/or size > 2.5 cm, DCISionRT combined with a novel response subtype biosignature (Rst) identified an elevated risk group with two distinct subtypes of women: (1) a poor Rst that had high IBTR/IBC rates with or without RT and (2) a good Rst deriving significant benefit from adjuvant RT. Women in the corresponding low risk group had low 10-year IBTR/IBC rates and derived no significant benefit from adjuvant RT.

To compare the risk of subclinical breast cancer-related lymphedema (sBCRL) using bioimpedance spectroscopy (BIS) or tape measure (TM) by the extent of axillary surgery and regional nodal irradiation (RNI).Patients were randomized to surveillance with TM or BIS. A BIS ≥6.5 L-Dex units or TM volume change ≥5 and10% above presurgical baselines "triggered" sBCRL. The incidence of sBCRL by sentinel node biopsy or axillary lymph node dissection (ALND) with or without RNI was examined for 484 patients. Radiation was categorized as "limited RNI" (axilla level I/II only) or "extensive RNI" (axilla level III or supraclavicular fossa with or without level I/II).At a median follow-up of 20.5 months, 109 of 498 patients (21.9%) triggered sBCRL (BIS 13.5% vs TM 25.6%; P.001). In patients not receiving RNI, BIS triggered 12.9% of patients undergoing SNB and 25.0% undergoing ALND (P = .18). Extensive RNI significantly increased triggering with BIS versus no RNI after sentinel node biopsy (SNB; 33.3% vs 12.9%; P = .03) but not ALND (30.8% vs 25.0%; P = .69). Triggering by TM was greater than 25% for most subgroups and was inferior to BIS in discriminating the risk of sBCRL by utilization of RNI or axillary surgery.The lower triggering rates with BIS and its better discrimination of the risk of sBCRL by receipt and type of RNI compared with TM support its use for posttreatment surveillance to detect sBCRL and to initiate early intervention. The risk of sBCRL increased with more extensive axillary treatment. Patients having ALND or extensive RNI require close surveillance for BCRL. Longer follow-up is required to determine rates of progression to clinical lymphedema.

Background: We reviewed serial bioimpedance measurements in order to quantify the relationship between changes in these scores and a patient's risk for developing breast cancer-related lymphedema (BCRL). Methods and Results: From April 2010 through November 2016, 505 patients were prospectively evaluated using bioimpedance spectroscopy (BIS/L-Dex). Patients received preoperative and postoperative L-Dex measurements and were categorized based upon risk for BCRL with respect to axillary staging procedure, radiation use, taxane use, and body mass index (BMI). L-Dex change was associated with the type and number of BCRL risk factors. Both axillary lymph node dissection (ALND) and regional nodal irradiation (RNI) were associated with a greater change in L-Dex (p

Background: We report outcomes using prospective BIS surveillance in a high-risk cohort of patients who all underwent axillary lymph node dissection (ALND). Methods: From 8/2010 through 12/2016, 206 consecutive patients were evaluated with BIS as part of a prospective surveillance program. 30 underwent ALND and constitute the study population. The program included pre-operative BIS measurement as well as post-operative assessments at regular intervals. Patients with L-Dex readings increasing by more than 10 from baseline were considered to have subclinical BCRL and treated with an over-the-counter (OTC) compression sleeve for 4 weeks. For the purpose of this analysis, additional high-risk features were defined as receipt of axillary radiation, a high body mass index (BMI) or the use of taxane based chemotherapy. Chronic BCRL was defined as the need for complex decongestive physiotherapy (CDP). Results: Median follow-up was 36 months (range: 4.8-122.1 months). The median number of nodes removed was 18 (range: 5-32) and the median number of positive nodes was two. The median age for the cohort was 57.5 years old with 70% of patients undergoing mastectomy and the remainder breast conserving therapy. With respect to additional high-risk features, 77% also received taxane-based chemotherapy, 62% axillary irradiation, and 48% had an elevated BMI. Overall, 86% of patients had at least one additional high-risk feature, 70% at least two, and 23% had all three additional high-risk features. Seven patients (23%) had an elevated L-Dex score at some point during follow-up and underwent intervention with an OTC sleeve for 4 weeks. To date, no patients have required CDP at any time. Conclusions: Prospective surveillance with BIS in a high-risk cohort of patients all undergoing ALND (plus additional high-risk features) led to no patients requiring CDP. These excellent findings are consistent with growing data supporting the use of BIS in prospective BCRL surveillance programs. Citation Format: Kaufman D, Shah C, Vicini F. Low rates of chronic breast cancer related lymphedema (BCRL) in a cohort of high-Risk patients undergoing prospective surveillance with bioimpedance spectroscopy (BIS) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-09.

Background: Electron intraoperative radiotherapy (IORT) can be used during breast conservation surgery to treat early-stage invasive breast cancer. While IORT may be an attractive alternative to traditional post-operative radiotherapy for many patients, its effectiveness in preventing local recurrence is still being evaluated. Using data from current clinical and observational studies, we aimed to assess the impact of single-fraction electron IORT on local recurrence rates. Methods: Studies on single-fraction electron IORT during breast conservation surgery were identified through a search of PubMed and Google Scholar, as well as secondary referencing. Local recurrence rate was the main outcome of interest. Protocols from each publication were assessed for potential sources of heterogeneity. A meta-analysis of proportions, using binomial distribution to model the within-study variability and a random effects model, was conducted to estimate a pooled local recurrence rate. In order to estimate a 5-year recurrence rate, we applied a single-sample Poisson-normal model to model the probability of events occurring during a fixed period of time (60 months). Results: A total of 13 independent publications were identified for abstraction. The analysis demonstrated a pooled monthly local recurrence rate of 0.02% per person-month (95% CI: 0.00 – 0.06%) for the studies with < 5 years of follow-up, 0.03% per person-month (0.02 – 0.06%) for studies with ≥ 5 years of follow-up, and 0.02% per person-month (0.01 – 0.04%) overall. Based on this model, the predicted 5-year recurrence rate is 2.7%, with a 95% confidence interval of 1.9% - 3.7%. Conclusions: According to the published literature, the rate of breast cancer local recurrence after electron IORT was 0.02% per person-month; with an adjusted 5-year recurrence rate of 2.7%. These findings support the recent guidelines from the American Society for Radiation Oncology (ASTRO) supporting the use of electron IORT in low-risk patients. Citation Format: Harness J, Shah C, Brooks E, Via C, Vicini F. Meta-analysis of local recurrence of invasive breast cancer after electron intraoperative radiotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-13.

Background: We evaluated the impact of structured surveillance using bioimpedance spectroscopy (BIS) to prevent clinical BCRL in a group of high-risk (axillary lymph node dissection) patients. Methods: From April 2010 through November 2016, 93 patients who were treated with axillary lymph node dissection (ALND) were prospectively monitored with BIS using L-Dex (Impedimed). Patients received a pre-operative baseline L-Dex measurement followed by post-operative assessments at regular intervals. An elevated L-Dex score was defined as an increase of ≥10 points above baseline (considered subclinical BCRL). Intervention consisted of applying an over the counter (OTC) sleeve for 4 weeks followed by re-evaluation. The need for complete decongestive physiotherapy (CDP) represented a surrogate for the development of clinically significant, chronic BCRL. Results: Median follow-up was 24 months (range: 0.3-206.4 months). The median number of nodes removed was 19 (range: 5-41) and the median number of positive nodes was 3. Median age was 53 years old. Eighty five percent of patients underwent mastectomy and the remainder breast conserving therapy. 55% of patients received taxane based chemotherapy, 24% received some form of axillary RT (15% high tangents and 9% comprehensive regional nodal RT) and 74% had an elevated body mass index (BMI, > 25). Overall, 75% of these patients had at least one additional high-risk feature, 48% had at least two, and 6% had 3 (either taxane chemotherapy, axillary RT or elevated BMI). Thirty-three patients (35.4%) developed an elevated L-Dex score at some point during follow up. Overall, 10 patients (11%) required CDP at any point after treatment. Conclusions: The results of this analysis support previously published data on the efficacy of prospective BCRL surveillance and early intervention using BIS. Of the 93 high-risk patients prospectively followed and managed in this structured BCRL protocol, 11% required CDP. These results compare favorably to all contemporary studies reporting BCRL rates in high-risk patients. Citation Format: Whitworth P, Cooper A, Shah C, Vicini F. The impact of a structured surveillance protocol using bioimpedance spectroscopy (BIS) on preventing breast cancer related lymphedema (BCRL) in high-Risk patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-08.

Background: With improved breast cancer outcomes, an increasing focus on sequelae of treatment as part of survivorship has emerged. Breast cancer related lymphedema (BCRL) represents one such sequelae. Increasing data and recent NCCN guidelines support the use of prospective BCRL surveillance to allow for early detection and intervention as a method to reduce chronic, irreversible BCRL. Therefore, this study was performed to evaluate the impact early detection and treatment of BCRL in breast cancer patients undergoing prospective surveillance with bioimpedance spectroscopy (BIS). Methods: From 8/2010 through 12/2016, 206 patients were evaluated with BIS as part of a prospective surveillance program.The protocol included pre-operative assessment with BIS as well as post-operative assessments with BIS at regular intervals. Patients with L-Dex readings increasing by more than 10 from baseline were considered to have subclinical BCRL and treated with a compression sleeve for 4 weeks. For the purpose of this analysis, high-risk was defined as receipt of ALND, regional nodal irradiation, or taxane chemotherapy. Chronic BCRL was defined as the need for complex decongestive physiotherapy. Results: A total of 206 patients were analyzed, with a mean age of 61 years old and a median follow up of 25.9 months. Overall, 17% of patients had least one high-risk feature, 8% had two factors, and 7% had all three factors. A total of 21 patients (9.8%) were diagnosed with subclinical BCRL. Increased rates of subclinical BCRL were seen in patients undergoing ALND (23% vs. 7%, p=0.01) with ALND and receipt of RNI associated with development of subclinical BCRL. At last follow-up, no patients had persistent, chronic BCRL following early, conservative intervention measures. Conclusions: The results of this study support prospective surveillance and early treatment utilizing BIS. Intervention triggered by subclinical BCRL detection with an elevated L-Dex score was associated with a very low rate of chronic BCRL. Citation Format: Kaufman D, Shah C, Vicini F. Utilization of bioimpedance spectroscopy in the prevention of chronic breast cancer related lymphedema [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-12-03.

This phase III post-NC trial evaluates if CWRNRT post-Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the IBCR-FI rate in pts with PPAx nodes that are pathologically negative after NC. Secondary aims are OS, LRR-FI, DR-FI, DFS-DCIS, second primary cancer, and comparison of RT effect on cosmesis in reconstructed Mx pts. Correlative science examines RT effect by tumor subtype, molecular outcome predictors for residual disease, and predictors for the degree of reduction in loco-regional recurrence. Methods: Clinical T1-3, N1 IBC PPAx nodes (FNA or core needle biopsy) pts complete ≥8 weeks of NC (anthracycline and/or taxane). HER2+ pts receive anti-HER2 therapy. Following NC, BCS or Mx, sentinel node biopsy (≥2 nodes) and/or Ax dissection with histologically negative nodes is performed. ER/PR and HER-2neu status before NC is required. Pts may receive appropriate adjuvant systemic therapy. Radiation credentialing with a facility questionnaire/case benchmark is required. Random assignment for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI+RNRT. Statistics: 1,636 pts are to be enrolled over 5 yrs (definitive analysis at 7.5 yrs). Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction of 4.6% (5-yr cumulative rate). Intent-to-treat analysis with 3 interim analyses (43, 86, and 129 events) and a 4th/final analysis at 172 events. Pt-reported outcomes focusing on RT effect will be provided by 736 pts before random assignment and at 3, 6, 12, and 24 mos. Accrual as of 6-21-18 is 967 (59.11%). Contacts: Protocol: CTSU member website https://www.ctsu.org. Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org. Pt entry: OPEN at https://open.ctsu.org or the OPEN tab on CTSU member website. NCT01872975 Support: U10 CA-2166; -180868, -180822; 189867; Elekta Citation Format: Mamounas EP, Bandos H, White JR, Julian TB, Khan AJ, Shaitelman SF, Torres MA, Vicini FA, Ganz PA, McCloskey SA, Paik S, Gupta N, Li XA, DiCostanzo DJ, Curran WJ, Wolmark N. Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to whole breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with pathologically positive axillary (PPAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC): NRG Oncology/NSABP B-51/RTOG 1304 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-04-01.

Purpose/Objective(s) Shorter courses of breast radiotherapy are offered as an alternative to 4-6 weeks of whole breast irradiation after lumpectomy, including brachytherapy. A prospective phase II multi-institution clinical trial to study 3-fraction accelerated partial breast irradiation (APBI) delivered by brachytherapy was conducted. Materials/Methods The trial treated selected breast cancers after breast-conserving surgery with brachytherapy applicators that delivered 22.5 Gy in 3 fractions of 7.5 Gy. The planning treatment volume was 1 to 2 cm beyond the surgical cavity. Eligible women were age ≥ 45 years with unicentric invasive or in situ tumors ≤ 3 cm excised with negative margins and with positive estrogen or progesterone receptors and no metastases to axillary nodes. Strict dosimetric parameters were required to be met and follow up information was collected from the participating sites. Results A total of 175 patients who were enrolled were followed for a median of 3.63 years. Three-fraction brachytherapy was associated with low chronic toxicity. There was excellent or good cosmesis in 95% of patients. There were no grade 4 toxicities. Grade 3 fibrosis at the treatment site was present in 1.7% and 32% percent had grades 1 or 2 fibrosis at the treatment site. There was 1 rib fracture. Other late toxicities included 7.4% grade 1 hyperpigmentation, 2% grade 1 telangiectasias, 1.7% symptomatic seromas, 1.7% abscessed cavities, and 1.1% symptomatic fat necrosis. There were 2 (1.1%) ipsilateral local recurrences, 2 (1.1%) nodal recurrences and no distant recurrences. Other incidents included one contralateral breast cancer and 2 second malignancies (lung). Conclusion Ultra-short breast brachytherapy is feasible and with acceptable late toxicity and could be an alternative to standard 5-day, 10 fraction APBI in eligible patients. Patients from this prospective trial will continue to be followed to evaluate long term outcomes.

PURPOSE/OBJECTIVE(S) Regional collaborative quality initiatives that incent participation through direct payment and streamlined reimbursement for high-performing sites have been shown to drive improvements in surgical outcomes. Numerous quality measures have been proposed in radiation oncology, and research has identified readily measurable indicators like dose to critical structures that predict for subsequent toxicity in patients. A decade ago, we initiated a voluntary statewide collaboration for quality improvement in radiation oncology and now describe its impact on care delivery. MATERIALS/METHODS Following SQUIRE guidelines, we describe the approach and measures that the program has implemented. To evaluate impact, we describe compliance at baseline and now with active measures among participating practices. RESULTS Since beginning data collection in 2012, radiation oncologists, physicists, data abstractors, and practice administrators from sites in one state (currently numbering 27) have convened thrice yearly. At these meetings, experts have spoken regarding trends within the field and inspired discussions regarding potential targets for quality improvement within the consortium. Blinded data on practices at various sites have also been regularly presented, and the group has iteratively developed new initiatives and consensus-based benchmarks to improve radiation oncology care delivery, patient experiences, and outcomes. An observational dataset with detailed information from over 20,000 patients has been assembled to evaluate quality. Compliance with select measures is described in the table, including use of guideline-concordant hypofractionated radiotherapy, motion management, doses to targets/normal tissues, and consistency in delineating and naming contoured structures (a precondition for quality evaluation). CONCLUSION Although observational analysis cannot fully exclude secular trends, contextual data revealing slow uptake of best practices elsewhere in the US suggests that this initiative has improved the consistency, efficiency, and quality of radiation oncology care in its member practices and may be a model for other regions.

In the original publication of the article, under the heading, Study limitations in the Discussion section, the second paragraph, fifth sentence was published incorrectly as “Patients with an L-Dex increase of ≥ 5.5 undergo…sleeve for 4 weeks”.

Purpose To investigate patterns of failure in institutional credentialing submissions to NRG/RTOG 1005 with the aim of improving the quality and consistency for future breast cancer protocols. Methods and Materials NRG/RTOG 1005 allowed the submission of 3-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), and simultaneous integrated boost (SIB) breast plans. Credentialing required institutions to pass a 2-step quality assurance (QA) process: (1) benchmark, requiring institutions to create a plan with no unacceptable deviations and ≤1 acceptable variation among the dose volume (DV) criteria, and (2) rapid review, requiring each institution's first protocol submission to have no unacceptable deviations among the DV criteria or contours. Overall rates, number of resubmissions, and reasons for resubmission were analyzed for each QA step. Results In total, 352 institutions participated in benchmark QA and 280 patients enrolled had rapid review QA. Benchmark initial failure rates were similar for 3DCRT (18%), IMRT (17%), and SIB (18%) plans. For 3DCRT and IMRT benchmark plans, ipsilateral lung most frequently failed the DV criteria, and SIB DV failures were seen most frequently for the heart. Rapid review contour initial failures (35%) were due to target rather than organs at risk. For 29% of the rapid review initial failures, the planning target volume boost eval volume was deemed an unacceptable deviation. Conclusions The review of the benchmark and rapid review QA submissions indicates that acceptable variations or unacceptable deviations for the ipsilateral lung and heart dose constraints were the most commonly observed cause of benchmark QA failure, and unacceptable deviations in target contouring, rather than normal structure contouring, were the most common cause of rapid review QA failure. These findings suggest that a rigorous QA process is necessary for high quality and homogeneity in radiation therapy in multi-institutional trials of breast cancer to ensure that the benefits of radiation therapy far outweigh the risks.

Summary Background Whole-breast irradiation after breast-conserving surgery for patients with early-stage breast cancer decreases ipsilateral breast-tumour recurrence (IBTR), yielding comparable results to mastectomy. It is unknown whether accelerated partial breast irradiation (APBI) to only the tumour-bearing quadrant, which shortens treatment duration, is equally effective. In our trial, we investigated whether APBI provides equivalent local tumour control after lumpectomy compared with whole-breast irradiation. Methods We did this randomised, phase 3, equivalence trial (NSABP B-39/RTOG 0413) in 154 clinical centres in the USA, Canada, Ireland, and Israel. Adult women (>18 years) with early-stage (0, I, or II; no evidence of distant metastases, but up to three axillary nodes could be positive) breast cancer (tumour size ≤3 cm; including all histologies and multifocal breast cancers), who had had lumpectomy with negative (ie, no detectable cancer cells) surgical margins, were randomly assigned (1:1) using a biased-coin-based minimisation algorithm to receive either whole-breast irradiation (whole-breast irradiation group) or APBI (APBI group). Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with or without a supplemental boost to the tumour bed, and APBI was delivered as 34 Gy of brachytherapy or 38·5 Gy of external bream radiation therapy in 10 fractions, over 5 treatment days within an 8-day period. Randomisation was stratified by disease stage, menopausal status, hormone-receptor status, and intention to receive chemotherapy. Patients, investigators, and statisticians could not be masked to treatment allocation. The primary outcome of invasive and non-invasive IBTR as a first recurrence was analysed in the intention-to-treat population, excluding those patients who were lost to follow-up, with an equivalency test on the basis of a 50% margin increase in the hazard ratio (90% CI for the observed HR between 0·667 and 1·5 for equivalence) and a Cox proportional hazard model. Survival was assessed by intention to treat, and sensitivity analyses were done in the per-protocol population. This trial is registered with ClinicalTrials.gov , NCT00103181 . Findings Between March 21, 2005, and April 16, 2013, 4216 women were enrolled. 2109 were assigned to the whole-breast irradiation group and 2107 were assigned to the APBI group. 70 patients from the whole-breast irradiation group and 14 from the APBI group withdrew consent or were lost to follow-up at this stage, so 2039 and 2093 patients respectively were available for survival analysis. Further, three and four patients respectively were lost to clinical follow-up (ie, survival status was assessed by phone but no physical examination was done), leaving 2036 patients in the whole-breast irradiation group and 2089 in the APBI group evaluable for the primary outcome. At a median follow-up of 10·2 years (IQR 7·5–11·5), 90 (4%) of 2089 women eligible for the primary outcome in the APBI group and 71 (3%) of 2036 women in the whole-breast irradiation group had an IBTR (HR 1·22, 90% CI 0·94–1·58). The 10-year cumulative incidence of IBTR was 4·6% (95% CI 3·7–5·7) in the APBI group versus 3·9% (3·1–5·0) in the whole-breast irradiation group. 44 (2%) of 2039 patients in the whole-breast irradiation group and 49 (2%) of 2093 patients in the APBI group died from recurring breast cancer. There were no treatment-related deaths. Second cancers and treatment-related toxicities were similar between the two groups. 2020 patients in the whole-breast irradiation group and 2089 in APBI group had available data on adverse events. The highest toxicity grade reported was: grade 1 in 845 (40%), grade 2 in 921 (44%), and grade 3 in 201 (10%) patients in the APBI group, compared with grade 1 in 626 (31%), grade 2 in 1193 (59%), and grade 3 in 143 (7%) in the whole-breast irradiation group. Interpretation APBI did not meet the criteria for equivalence to whole-breast irradiation in controlling IBTR for breast-conserving therapy. Our trial had broad eligibility criteria, leading to a large, heterogeneous pool of patients and sufficient power to detect treatment equivalence, but was not designed to test equivalence in patient subgroups or outcomes from different APBI techniques. For patients with early-stage breast cancer, our findings support whole-breast irradiation following lumpectomy; however, with an absolute difference of less than 1% in the 10-year cumulative incidence of IBTR, APBI might be an acceptable alternative for some women. Funding National Cancer Institute, US Department of Health and Human Services.

Purpose Shorter courses of accelerated partial-breast irradiation delivered as single-fraction intraoperative therapy are now offered as an alternative to 4 to 6 weeks of whole-breast irradiation after lumpectomy. However, this approach has potential shortcomings in patient selection and target volume definition and in dosimetric, radiobiological, and logistical issues. We designed a prospective, phase 2, multi-institution clinical trial to study 2- or 3-day accelerated partial breast irradiation delivered with brachytherapy applicators. Methods and Materials This trial treats select breast cancers after breast-conserving surgery with brachytherapy applicators that deliver 22.5 Gy in 3 fractions of 7.5 Gy. The planning treatment volume was 1 to 1.5 cm beyond the surgical cavity. Eligible women were aged ≥45 years with unicentric invasive or in situ tumors ≤3.0 cm with positive estrogen or progesterone receptors and no metastasis to axillary nodes that have been excised with negative margins. Strict dosimetric parameters were required to be met before acceptance into the trial. Results A group of 200 patients was prospectively enrolled and followed for a minimum of 6 months. Two- or 3-day brachytherapy was associated with low acute or subacute toxicity, 97.25% excellent or good cosmetic outcomes, and excellent local control in select breast cancers. Conclusions Ultrashort breast brachytherapy is dosimetrically feasible and can be delivered with excellent short-term tolerance and low toxicity.

Background: The goal of therapy for DCIS is to prevent invasive breast cancer. Randomized clinical trials for DCIS demonstrated that patients benefited from adjuvant radiation therapy (RT) after breast conserving surgery (BCS). However, treatment selection for patients with DCIS remains a challenge. Studies evaluating ‘low-risk’ clinicopathologic features have not identified a group of patients who do not benefit significantly from RT after BCS. Recently, a biosignature, DCISionRT (PreludeDx, Laguna Hills, CA), has been validated in multiple cohorts. The test provides a continuous 10-year breast event risk for patients treated with and without RT after BCS. In this study, we examined the utility of the biosignature to identify patients who met RTOG 9804 or ECOG 5194 ‘low-risk’ criteria but remained at elevated invasive risk after BCS and benefited from RT. Methods: The analysis was performed in a combined cohort made up of four studies. FFPE tissue samples and patient outcomes were obtained from Uppsala University Hospital and Västmanland County Hospital, Sweden (UUH) between 1986 and 2004, the University of Massachusetts, Worcester (UMass) from 1999 to 2008, from Kaiser Permanente Northwest (KPNW) from 1990-2007, and from the SweDCIS trial cohort (1987-2000). Patients were treated with or without RT after BCS. Treatment decisions were neither randomized nor strictly rules-based, except for the randomized SweDCIS trial for RT. Individual patient outcome and biosignature results were analyzed independently at University of South Florida. Hazard ratios (HR) were determined using Cox proportional hazards analyses, and 10-year risks were assessed with survival analysis. Results: Complete biomarker and clinical data was available for 660 women meeting a ‘low-risk’ clinico-pathologic criteria like ECOG 5194 grade 1 or 2 and for 535 women meeting RTOG 9804 like criteria. In this subset, there were 49 invasive breast cancer events for ECOG 5194 and 38 for RTOG 9804 within 10 years of diagnosis. In the biosignature low risk group there was no significant reduction from RT (p>0.15), where the 10-year absolute invasive benefit from RT varied from 1% to 2% for patients meeting RTOG 9804 or ECOG 5194, Table 1. However, in the biosignature elevated risk group, RT significantly reduced invasive cancer risk (p 100 for RTOG 9804 like criteria, while the NNT was 7 in the biosignature elevated risk group. Conclusions: The DCIS biosignature identified patients from four cohorts that met ‘low-risk’ clinicopathologic criteria like RTOG 9804 or ECOG 5194 grade 1 or 2, and had elevated 10-year risk after BCS but had a substantial 84% relative benefit from RT. In contrast, the biosignature also identified a low risk group of patients with who had minimal (1-2%) risk reduction from RT. In comparison with traditional clinicopathologic features used to make RT recommendations, the DCISionRT score was dramatically associated with RT therapy benefit. Biosignature low risk group (DS Biosignature elevated risk group (DS>3)patients, nevents, n10-year invasive risk difference, %10-year Invasive Cancer Risk, %+/- RT+/- RTNo RT - RTNo RTRTRTOG98042391515.017.92.9ECOG 5194 (Grade 1-2)3162311.815.94.2(p>0.15) Citation Format: Frank Vicini, Chirag Shah, Steven Shivers, Weiwei He, Per Karlsson, Erik Holmberg, Michael C Leo, Yangxin Huang, Sheila Weinmann, Fredrik Warnberg, Troy Bremer. DCIS biosignature reclassified patients who met RTOG 9804 or ECOG-ACRIN E5194 ‘low-risk’ clinicopathologic criteria into an elevated invasive risk group who benefited significantly from radiation therapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD5-04.

Purpose NRG Oncology RTOG 0319 was the first cooperative group trial in the United States to evaluate 3-dimensional conformal radiation therapy (3D-CRT) accelerated partial breast irradiation (APBI). This report updates secondary endpoints of toxicity and efficacy. Methods and Materials Patients with stage I or II invasive breast cancer (tumor size ≤3 cm, ≤3 positive lymph nodes, negative margins) were eligible for 3D-CRT APBI: 38.5 Gy in 10 twice-daily fractions. Patient characteristics and treatment details have previously been reported. Adverse events were graded with CTCAE v3.0 (National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0). This analysis updates the rates of ipsilateral breast recurrence (IBR), contralateral breast recurrence, ipsilateral node recurrence (INR), metastatic sites (distant metastases [DM]), mastectomy, disease-free survival, mastectomy-free survival, and overall survival. Results Of 58 enrolled patients, 52 were eligible, with a median age of 61 years; 94% had stage I cancer and 83% had estrogen receptor positive disease. The median follow-up period was 8 years (minimum-maximum, 1.7-9.0 years). The 7-year estimate of isolated IBR (no DM) was 5.9%. The 7-year estimates of all IBRs, INR, mastectomy rate, and DM were 7.7%, 5.8%, 7.7%, and 7.7%, respectively. All 4 IBRs were invasive, of which 3 had a component within the planning target volume. The patterns of failure were as follows: 3 IBRs, 1 INR, 2 DM, 1 INR plus DM, and 1 IBR plus INR plus DM. The 7-year estimates of mastectomy-free survival, disease-free survival, and overall survival were 71.2%, 71.2%, and 78.8%, respectively. Thirteen patients died: 3 of breast cancer and 10 of other causes. Grade 3 (G3) treatment-related adverse events were reported by 4 patients (7.7%). No G3 pain or pulmonary or cardiac toxicities were reported. Conclusions This phase 1 and 2 trial of 3D-CRT APBI continues to show durable tumor control and minimal G3 toxicity, comparable to other APBI techniques. Mature phase 3 results will determine the appropriateness and limitations of this noninvasive APBI technique.

To examine 10-year rates of local, regional, and distant recurrences, patterns of recurrence, and survival rates for breast cancer patients enrolled on Study NRG Oncology/Radiation Therapy Oncology Group 9517, a multi-institutional prospective trial that studied one of the earliest methods of accelerated partial breast irradiation (APBI), multicatheter brachytherapy (MCT).Eligibility included stage I/II unifocal breast cancer3 cm in size after lumpectomy with negative surgical margins and 0 to 3 positive axillary nodes without extracapsular extension. The APBI dose delivered was 34 Gy in 10 twice-daily fractions over 5 days for high-dose-rate (HDR); and 45 Gy in 3.5 to 5 days for low-dose-rate (LDR) brachytherapy. The primary endpoint was HDR and LDR MCT reproducibility. This analysis focuses on long-term ipsilateral breast recurrence (IBR), contralateral breast cancer events (CBE), regional recurrence (RR), and distant metastases (DM), disease-free, and overall survival.The median follow-up was 12.1 years. One hundred patients were accrued from 1997 to 2000; 98 were evaluable; 65 underwent HDR and 33 LDR MCT. Median age was 62 years; 88% had T1 tumors; 81% were pN0. Seventy-seven percent were estrogen receptor and/or progesterone receptor positive; 33% received adjuvant chemotherapy and 64% antiendocrine therapy. There have been 4 isolated IBRs and 1 IBR with RR, for 5.2% 10-year IBR without DM. There was 1 isolated RR, 1 with IBR, and 1 with a CBE, for 3.1% 10-year RR without DM. The 10-year CBE rate was 4.2%, with 5 total events. Eleven patients have developed DM, 8 have died of breast cancer, and 22 have died from other causes. The 10-year DFS and OS rates are 69.8% and 78.0%, respectively.This multi-institutional, phase 2 trial studying MCT-APBI continues to report durable in-breast cancer control rates with long-term follow-up.

Accelerated partial breast irradiation (APBI) represents an evolving technique that is a standard of care option in appropriately selected woman following breast conserving surgery. While multiple techniques now exist to deliver APBI, interstitial brachytherapy represents the technique used in several randomized trials (National Institute of Oncology, GEC-ESTRO). More recently, many centers have adopted applicator-based brachytherapy to deliver APBI due to the technical complexities of interstitial brachytherapy. The purpose of this article is to review methods to evaluate and select patients for APBI, as well as to define potential workflow mechanisms that allow for the safe and effective delivery of APBI. Multiple consensus statements have been developed to guide clinicians on determining appropriate candidates for APBI. However, recent studies have demonstrated that these guidelines fail to stratify patients according to the risk of local recurrence, and updated guidelines are expected in the years to come. Critical elements of workflow to ensure safe and effective delivery of APBI include a multidisciplinary approach and evaluation, optimization of target coverage and adherence to normal tissue guideline constraints, and proper quality assurance methods.

Objective: Patient-reported toxicities after breast radiotherapy merit understanding in order to inform decisions and target supportive care interventions. Methods: As part of a collaborative quality improvement initiative, the Michigan Radiation Oncology Quality Consortium prospectively collects patient-reported outcomes data from women treated for breast cancer at 26 practices across the state. Of all 11,107 patients treated with lumpectomy and whole breast radiation therapy between 1/1/2012 and 12/31/2018, 2817 refused patient surveys. We describe here the maximal toxicity reported by the 7689 patients who provided survey responses within 7 days of end of treatment and for whom we had sufficient data to determine dose-fractionation and treatment fields. Multivariable logistic regression models separately identified the individual and treatment characteristics associated with 1) breast pain, 2) a bother scale (related to itching, stinging/burning, swelling, or hurting of the treated breast), and 3) fatigue. Breast pain was considered moderate or severe when score ≥4 on modified 10-point Brief Pain Inventory measure. Bother from multiple breast symptoms was considered frequent when score ≥3 on a scaled measure (range 0-4) averaging responses on four items derived from the Skindex. Fatigue was considered severe when rated as present “always” or “most of the time” over past four weeks. Results: Moderate or severe breast pain was reported by 2882 (37.5%) overall: 1022 (28.3%) of those receiving hypofractionation (HF) and 1860 (45.7%) of those receiving conventional fractionation (CF). Frequent bother from multiple breast symptoms was reported by 1029 (13.4%) overall: 288 (8.0%) after HF and 741 (18.2%) after CF. Severe fatigue was reported by 1795 (23.4%) overall: 681 (18.8%) after HF and 1114 (27.4%) after CF. In addition to treatment fractionation (p Conclusions: In this large observational dataset of patient-reported toxicities after whole breast radiotherapy, substantial differences existed by radiotherapy dose-fractionation. Race differences in breast pain and bother existed despite controlling for multiple other factors, including age, body habitus, comorbidities, and treatment characteristics; further research is needed to understand what drives these differences in order to target potentially modifiable factors. Intensification of supportive care may be appropriate for subgroups identified as being vulnerable to greater toxicity. Multivariable Models of Patient-Reported Toxicity OutcomesIndependent VariableOdds Ratio (CI) [p value] in Model with Dependent Variable=Moderate or Severe Breast PainOdds Ratio (CI) [p value] in Model with Dependent Variable=Frequent Bother from Multiple Breast SymptomsOdds Ratio (CI) [p value] in Model with Dependent Variable=Severe FatigueAge 70+ vs 60-690.77 (0.67 - 0.89) [p40 vs Overweight 25- Citation Format: Reshma Jagsi, Kent Griffith, Frank Vicini, Jay Burmeister, Michael Dominello, Inga Grills, James Hayman, Jean Moran, Peter Paximadis, Jeffrey Radawski, Eleanor Walker, Lori Pierce. Identifying patients at higher risk of toxicity after breast radiotherapy: Analysis of patient-reported outcomes in the Michigan Radiation Oncology Quality Consortium cohort [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD6-6.

Background: Data regarding pretreatment, bioimpedance spectroscopy (BIS) L-Dex(®) values for patients newly diagnosed with breast cancer, and longitudinal data 12 months postoperatively are lacking. This study describes L-Dex values at the time of breast cancer diagnosis and maximum L-Dex change within 12 months of surgery. Methods and Results: Patients were enrolled in a parent, clinical trial that compares the effectiveness of BIS for early detection of breast cancer-related lymphedema to tape measurement. A total of 280 women with a pretreatment and at least one postoperative L-Dex measurement (within 12 months of surgery) were included. Pretreatment L-Dex readings were compared with population norms and maximum L-Dex changes within 12 months were examined. An L-Dex U400 device was used to obtain BIS measurements. The documented normative mean value using this device is 0.00, which is at the 49th percentile for this sample. Approximately 6% of patients had a pretreatment L-Dex value of ≥7.0; 1.8% had an L-Dex value ≥10.0. For 12 months, 17.1% (n = 48) of patients had a maximum change in L-Dex value from pretreatment of ≥7.0 L-Dex units, suggestive of clinical lymphedema. Conclusions: At the time of breast cancer diagnosis, L-Dex values are similar to normative values. Identified maximum changes in L-Dex values 12 months postoperatively suggest that frequent L-Dex measurements during that time frame are of potential clinical benefit. Our findings are consistent with research supporting an L-Dex value of ≥7 as indicative of clinical lymphedema with subclinical lymphedema logically occurring at somewhat lower likely, near ≥6.5.

Purpose: We evaluated the impact of structured surveillance using bioimpedance spectroscopy (BIS) to reduce the rate of chronic breast cancer related lymphedema (BCRL) in high-risk patients undergoing axillary lymph node dissection (ALND). Methods: From April 2010 through November 2016, 93 patients who underwent ALND were prospectively monitored with BIS using L-Dex. Intervention for an L-Dex increase of > 10 consisted of applying an over the counter (OTC) sleeve followed by re-evaluation after 4 weeks. The utilization of complete decongestive physiotherapy (CDP) represented a surrogate for chronic BCRL. Results: Median follow-up was 24 months. 55% of patients received taxane-based chemotherapy, 24% received some form of regional nodal irradiation (RNI- includes additional fields or high tangents) and 74% had an elevated body mass index (BMI) with the median number of nodes removed being 19. Overall, 75% of these patients had at least one additional high-risk feature (taxane chemotherapy, RNI, elevated BMI), 48% had at least two, and 6% had all. Thirty-three patients (35.4%) developed an elevated L-Dex score with only 10 (10.8%) requiring CDP (30.3% of those undergoing treatment with sleeve). At last follow-up, only three patients (3%) had unresolved BCRL. Conclusions: The results of this analysis support previous data regarding prospective BCRL surveillance and early intervention using BIS. With this approach, only 3% of patients have chronic BCRL.

Ductal carcinoma in-situ (DCIS) of the breast has rapidly increased in incidence over the past several decades secondary to an increased use of screening mammography. Local treatment options for women diagnosed with DCIS include mastectomy or breast-conserving therapy (BCT). While several randomized trials have confirmed a greater than 50% reduction in the risk of local recurrence with the administration of radiation therapy (RT) compared to breast-conserving surgery (BCS) alone, controversy persists regarding whether or not RT is needed in selected ‘low-risk’ patients. Over the past two decades, two prospective single-arm studies and one randomized trial have been performed and confirm that the omission of RT after surgery alone is associated with higher rates of local recurrence even after selecting patients with the most optimal clinical and pathologic features. Importantly, these trials have failed to consistently and reproducibly identify a low-risk cohort of patients (based on clinical and pathologic features) that does not benefit from RT. As a result, adjuvant RT is still advocated in the majority of patients, even in these low-risk cases. Future research is moving beyond traditional clinical and pathologic risk factors and instead employing more modern approaches such as multi-gene assays and biomarkers with the hopes of identifying truly low-risk patients who may not require RT. However, recent studies confirm that even low-risk patients identified from multi-gene assays have higher rates of local recurrence with local excision alone than would be expected with the addition of radiation therapy.

Purpose Radiation Therapy Oncology Group (RTOG) 95-17, a Phase II trial to evaluate multicatheter brachytherapy (mCathBrachy) as the sole method of radiation therapy for Stage I–II breast cancer (BrCa), was the first cooperative group trial in North America to evaluate accelerated partial breast irradiation (APBI) and include patient-reported outcomes (PROs). This report presents the year-5 toxicity and cosmesis data. Methods and Materials After lumpectomy and axillary dissection for invasive BrCa (tumor size Results Grade (G) 1–2 skin toxicity developed in 78% of the pts and G3 in 13% (no G4). The tx effects included skin dimpling/indentation (37%), fibrosis (45%), telangiectasias (45%), skin catheter marks (54%), and symptomatic fat necrosis (15%). Breast asymmetry was reported in 73%. Rates of excellent-to-good cosmesis were similar between PROs (66%) and radiation oncologists (68%). The PROs of tx satisfaction at year-5 was 75%. Conclusions RTOG 95-17 documents the year-5 skin toxicity and tx effects of mCathBrachy APBI, which are associated with PROs of good-to-excellent cosmesis and high tx satisfaction. This emphasizes the importance of PROs when assessing BrCa tx. National Surgical Adjuvant Breast and Bowel Project B39/RTOG 0413 will allow for definitive comparisons between APBI and whole breast radiation therapy.

Background: This phase III post-NC trial evaluates if CWRNRT post-Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the IBCR-FI rate in pts with PAx nodes that are negative after NC. Secondary aims are OS, LRR-FI, DR-FI, DFS-DCIS, second primary cancer, and comparison of RT effect on cosmesis in reconstructed Mx pts. Correlative science examines RT effect by tumor subtype, molecular outcome predictors for residual disease pts, and predictors for the degree of reduction in locoregional recurrence. Methods: Clinical T1-3, N1 IBC PAx nodes (FNA or core needle biopsy) pts complete ≥8 weeks of NC (anthracycline and/or taxane). HER2+ pts receive anti-HER2 therapy. Following NC, BCS or Mx, sentinel node biopsy (≥2 nodes) and/or Ax dissection with histologically negative nodes is performed. ER/PR and HER-2neu status before NC is required. Pts receive required systemic therapy. Radiation credentialing with a facility questionnaire/case benchmark is required. Random assignment for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI+RNRT. Statistics: 1636 pts to be enrolled over 5 yrs (definitive analysis at 7.5 yrs). Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction of 4.6% (5-yr cumulative rate). Intent-to-treat analysis with 3 interim analyses (43, 86, and 129 events) and a 4th/final analysis at 172 events. Pt-reported outcomes focusing on RT effect will be provided by 736 pts before random assignment and at 3, 6, 12, and 24 mos. Accrual as of 6-12-17 is 645 (39.43%). Contacts: Protocol: CTSU member website https://www.ctsu.org. Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org. Pt entry: OPEN at https://open.ctsu.org or the OPEN tab on CTSU member website. Support: U10 CA-2166; -180868, -180822; 189867; Elekta. Citation Format: Mamounas EP, Bandos H, White JR, Julian TB, Khan AJ, Shaitelman SF, Torres MA, Vicini FA, Ganz PA, McCloskey SA, Paik S, Gupta N, Li XA, DiCostanzo DJ, Curran Jr WJ, Wolmark N. NRG oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with positive axillary (PAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-03-02.