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Patients with breast cancer and ipsilateral axillary and internal mammary (IM) lymph node involvement (cN3b) often forgo IM node resection. Therefore, radiation is important for curative therapy. However, prognosis is not well described in the era of modern systemic therapy, and limited data exist to guide optimal locoregional treatment recommendations.We retrospectively reviewed 117 patients with nonmetastatic cN3b breast cancer treated at our institution between 2014 and 2019. Staging included ultrasound evaluation of all regional nodal basins. All patients received neoadjuvant chemotherapy, resection of the breast primary, and axillary nodal dissection, followed by adjuvant radiation to the breast/chest wall and regional nodes. Institutional guidelines recommend a 10-Gy boost to radiographically resolved nodes, and a 16-Gy boost to unresolved nodes. Overall survival, recurrence-free survival (RFS), locoregional RFS, internal mammary RFS, and distant metastasis-free survival were evaluated with Kaplan-Meier analysis. A multivariable model for RFS was constructed.Median follow-up for 117 patients was 3.82 years. Median age at diagnosis was 46 years and 56 patients (48%) were receptor group ER+/HER2-. Mastectomy was performed in 96 patients (82%), 38 (32%) had biopsy-confirmed IMC involvement, and 8 (7%) had IM node dissection. The median initial radiation dose was 50 Gy (range, 50-55 Gy) and IMC boost 10 Gy (range, 0-16 Gy). The 5-year overall survival, IM RFS, locoregional RFS, distant metastasis-free survival, and RFS were 74%, 98%, 89%, 68%, and 67%, respectively. On multivariable analysis, a clinical complete response of the IM nodes or ypN0 (pathologic complete response of nodes) status had improved 5-year RFS with hazard ratios of 0.24 (P = .006) and 0.27 (P = .05), respectively. Extranodal extension or lymphovascular invasion were associated with worse 5-year RFS with hazard ratios of 4.13 (P = .001) and 2.25 (P = .04), respectively.Multimodality therapy provides excellent locoregional control of 89% at 5 years for patients with cN3b breast cancer. Adjuvant radiation yields a 5-year IM RFS of 98%. Clinical and pathologic response of IM nodes are independently prognostic for RFS.

Background: Inflammatory breast cancer (IBC) is a rare and highly aggressive form of breast cancer. Patients with IBC still have worse clinical outcomes compared to patients with non-IBC (40% versus 63% for 5 years overall survival, respectively) despite advances in breast cancer treatment. IBC remains a poorly characterized disease lacking specific therapeutic targets and prognostic biomarkers. Our group demonstrated that N-myc downstream regulated gene 1 (NDRG1) is crucial in promoting tumorigenesis and brain metastasis in mouse models of IBC. Our hypothesis is that NDRG1 is a prognostic marker associated with poor outcome in IBC patients. Methods: 64 IBC patients in a tissue microarray were evaluated by immunohistochemical staining with anti-NDRG1 primary antibody and NDRG1 levels were quantified. Using the median value, 32 patients were grouped as NDRG1-low (≤ median), and 32 as NDRG1-high (>median). Survival data were compared by Kaplan–Meier curves and log-rank test. Results: The average age of patients was 50 years. Sixty-two percent of patients had estrogen receptor (ER)-negative tumors, 83% were stage III, 80% high grade, and 67% of these patients received adjuvant radiation. The median follow-up time for the patients studied was 11.7 years, and the median overall survival (OS) time was 3.7 years. On univariate analysis, NDRG1 expression, tumor grade, disease stage, ER status, and adjuvant radiation therapy were associated with OS and disease specific survival (DSS). Patients with NDRG1-low tumors experienced better actuarial 10-year OS (p=0.0129) and DSS (p=0.0074), and showed significant higher 10-year OS and DSS rates than patients with NDRG1-high(OS, 45% vs. 19%, p=0.0278; DSS, 52% vs. 22%, p=0.0139). The median OS and DSS times were shorter for NDRG1-high patients (OS, 2.5 years; DSS, 3.1 years) than for NDRG1-low patients (OS, 5.9 years; DSS, 10.7 years). Multivariable analysis, NDRG1 was an independent predictor of OS (hazard ratio [HR]=2.449, p=0.0274) and DSS (HR=2.727, p=0.0039). ER status, disease stage and adjuvant radiation were also independent predictor for both OS and DSS. Furthermore, we observed that NDRG1-high expressing ER-negative tumors exhibit worse outcome in IBC patients (OS, p=0.0003; DSS, p=0.0003). NDRG1-high expression correlated with worse outcome in patients that received adjuvant radiation treatment (OS, p=0.0088; DSS, p=0.0093), and those with stage III (OS, p=0.0450; DSS, p=0.0239). Conclusions: Our findings demonstrated that NDRG1 is positively correlated with aggressive tumor characteristics in IBC and that it is an independent prognostic factor for OS and DSS in IBC patients, suggesting that targeting NDRG1 may provide a novel therapeutic strategy to improve outcomes for patients with IBC. Our data further suggests that NDRG1 warrants further investigation in radiation response. Citation Format: Emilly Schlee Villodre, Yun Gong, Xiaoding Hu, Lei Huo, Esther C Yoon, Naoto T Ueno, Wendy A Woodward, Debu Tripathy, Juhee Song, Bisrat G Debeb. NDRG1 expression is an independent prognostic factor in inflammatory breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-13.

Background. Lymphovascular invasion (LVI) and breast tumor emboli within dermal and breast lymphatic vessels are prognostic for metastatic spread and poor outcomes, and are abundant in Inflammatory breast cancer (IBC). IBC is an aggressive breast cancer that presents suddenly with breast swelling and redness due to tumor emboli in lymphatics. Lack of breast-feeding and obesity are IBC risk factors. We sought to demonstrate the combinatorial effects of a high-fat diet and nursing on lymphatic function and compare these to IBC tumor induced changes in lymphatic function. We hypothesize that risk factors for aggressive breast cancer may alter lymphatic function in the normal gland prior to tumor initiation. Methods. Following two rounds of pregnancy in 20 multiparous SCID Beige immunocompromised mice, half of the mice were force weaned while half nursed pups. Prior to forced weaning, half of each of these groups were fed a high fat diet (HFD: 60 Kcal %, N = 10) while the other half received a low-fat diet (LFD: 10 Kcal %, N = 10). Consecutive dynamic near-infrared fluorescence (NIRF) lymphatic imaging was performed at 6-7 months (covid interruption) and 14 months after initiating the diet by injecting a near-IR fluorophore into the mammary fatpad and recording lymphatic pulsing over 8 minutes using V++. Matlab and ImageJ were used to quantify pulsing rates on the ventral lymphatics in each animal. Fatpads were subsequently inoculated with SUM149 IBC cells and imaging was repeated 16 months post diet initiation. Lymphatic imaging over time by HFD vs LFD was further studied in nulliparous animals. Tissues were collected for further analyses. ResultsData analysis prior to tumor injection, demonstrated lymphatic pulsing (pulses/4 minutes) increased over time in HFD force weaned (HFFW) and HFD nursing (HFN) animals only (65.5 vs 72.6, P=0.059; 60.1 vs 76.6, P=0.0099, respectively). Comparing HFFW and HFN to matched LFD groups (LFFW and LFN), at 14 weeks HFD was associated with increased pumping after forced weaning (62.3 vs. 72.6, P=0.074), and nursing (62.5 vs 76.6, P=0.0023). There was an increase in pulsing after tumor initiation (16 months after initiation of diet) in all groups (80.1, 84.1, 83.2, 82.4, P > 0.05 all comparisons to initial timepoint). In a separate experiment examining HFD (N=5) vs LFD (N=5) in nulliparous mice, lymphatic contractile activity increased in all animals over. time, average ventral lymphatic contractile frequency for LFD and HFD at week 8,11 and 14 weeks after diet initiation were 5, 8.64, 15.9 pumps/4 mins vs 11.8, 18.5, 28.2 pumps/4 mins, (P = 0.01, 0.05, and 0.0005 respectively). ConclusionsHFD increased lymphatic pulsing rate over time to a significantly greater extent than LFD continuing over 14 months independent of reproductive and nursing status. Tumor initiation prompted further increased pulsing rates beyond that observed after HFD across all groups. The magnitude of the effect of HFD on lymphatic pulsing approached the rate after tumor initiation, while reproductive variables did not impact lymphatic pulsing. Further studies are warranted to demonstrate the relationship if any between lymphatic pumping pre-initiation and LVI after tumor initiation and examine the role of intervention on reducing LVI. Citation Format: Wintana Balema, Janelle Morton, Richard Larson, Fred C Velasquez, Eva Sevick-Muraca, Wendy A Woodward. Risk factor modeled microenvironment effects lymphatics activity and IBC invasiveness and progression [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-24-06.

Purpose BRCA1/2 pathogenic variant (PV) mutations confer radiation sensitivity preclinically, but there are limited data regarding breast cancer outcomes after radiation therapy (RT) among patients with documented BRCA1/2 PV mutations versus no PV mutations. Methods and Materials This retrospective cohort study included women with clinical stage I-III breast cancer who received definitive surgery and RT and underwent BRCA1/2 genetic evaluation at the The University of Texas MD Anderson Cancer Center. Rates of locoregional recurrence (LRR), disease-specific death (DSD), toxicities, and second cancers were compared by BRCA1/2 PV status. Results Of the 2213 women who underwent BRCA1/2 testing, 63% self-reported their race as White, 13.6% as Black/African American, 17.6% as Hispanic, and 5.8% as Asian/American Indian/Alaska Native; 124 had BRCA1 and 100 had BRCA2 mutations; and 1394 (63%) received regional nodal RT. The median follow-up time for all patients was 7.4 years (95% confidence interval [CI], 7.1-7.7 years). No differences were found between the groups with and without BRCA1/2 PV mutations in 10-year cumulative incidences of LRR (with mutations: 11.6% [95% CI, 7.0%-17.6%]; without mutations: 6.6% [95% CI, 5.3%-8.0%]; P = .466) and DSD (with mutations: 12.3% [95% CI, 8.0%-17.7%]; without mutations: 13.8% [95% CI, 12.0%-15.8%]; P = .716). On multivariable analysis, BRCA1/2 status was not associated with LRR or DSD, but Black/African American patients (P = .036) and Asians/American Indians/Alaska Native patients (P = .002) were at higher risk of LRR compared with White patients, and Black/African American patients were at higher risk of DSD versus White patients (P = .004). No in-field, nonbreast second cancers were observed in the BRCA1/2 PV group. Rates of acute and late grade ≥3 radiation-related toxicity in the BCRA1/2 PV group were 5.4% (n = 12) and 0.4% (n = 1), respectively. Conclusions Oncologic outcomes in a diverse cohort of patients with breast cancer who had a germline BRCA1/2 PV mutation and were treated with RT were similar to those of patients with no mutation, supporting the use of RT according to standard indications in patients with a germline BRCA1/2 PV mutation.

PURPOSE: There are limited prospective data on predictors of patient-reported outcomes (PROs) after whole-breast irradiation (WBI) plus a boost. We sought to characterize longitudinal PROs and cosmesis in a randomized trial comparing conventionally fractionated (CF) versus hypofractionated (HF) WBI. METHODS AND MATERIALS: From 2011 to 2014, women aged ≥40 years with Tis-T2 N0-N1a M0 breast cancer who underwent a lumpectomy with negative margins were randomized to CF-WBI (50 Gray [Gy]/25 fractions plus boost) versus HF-WBI (42.56 Gy/16 fractions plus boost). At baseline (pre-radiation), at 6 months, and yearly thereafter through 5 years, PROs included the Breast Cancer Treatment Outcome Scale (BCTOS), Functional Assessment of Cancer Therapy−Breast (FACTB), and Body Image Scale; cosmesis was reported by the treating physician using Radiation Therapy Oncology Group cosmesis values. Multivariable mixed-effects growth curve models evaluated associations of the treatment arm and patient factors with outcomes and tested for relevant interactions with the treatment arm. RESULTS: A total of 287 patients were randomized, completing a total of 14,801 PRO assessments. The median age was 60 years, 37% of patients had a bra cup size ≥D, 44% were obese, and 30% received chemotherapy. Through 5 years, there were no significant differences in PROs or cosmesis by treatment arm. A bra cup size ≥D was associated with worse BCTOS cosmesis (P < .001), BCTOS pain (P = .001), FACT-B Trial Outcome Index (P = .03), FACT-B Emotional Well-being (P = .03), and Body Image Scale (P = .003) scores. Physician-rated cosmesis was worse in patients who were overweight (P = .02) or obese (P < .001). No patient subsets experienced better PROs or cosmesis with CF-WBI. CONCLUSIONS: Both CF-WBI and HF-WBI confer similar longitudinal PROs and physician-rated cosmesis through 5 years of follow-up, with no relevant subsets that fared better with CF-WBI. This evidence supports broad adoption of hypofractionation with boost, including in patients receiving chemotherapy and in a population with a high prevalence of obesity. The associations of large breast size and obesity with adverse outcomes across multiple domains highlight the opportunity to engage at-risk patients in lifestyle intervention strategies, as well as to consider alternative radiation treatment regimens.

Inflammatory breast cancer (IBC) is an aggressive form of primary breast cancer characterized by rapid onset and high risk of metastasis and poor clinical outcomes. The biological basis for the aggressiveness of IBC is still not well understood and no IBC‐specific targeted therapies exist. In this study, we report that lipocalin 2 (LCN2), a small secreted glycoprotein belonging to the lipocalin superfamily, is expressed at significantly higher levels in IBC vs non‐IBC tumors, independently of molecular subtype. LCN2 levels were also significantly higher in IBC cell lines and in their culture media than in non‐IBC cell lines. High expression was associated with poor‐prognosis features and shorter overall survival in IBC patients. Depletion of LCN2 in IBC cell lines reduced colony formation, migration, and cancer stem cell populations in vitro and inhibited tumor growth, skin invasion, and brain metastasis in mouse models of IBC. Analysis of our proteomics data showed reduced expression of proteins involved in cell cycle and DNA repair in LCN2‐silenced IBC cells. Our findings support that LCN2 promotes IBC tumor aggressiveness and offer a new potential therapeutic target for IBC., In this study, the authors demonstrate that lipocalin 2 (LCN2) is highly upregulated in inflammatory breast cancer (IBC), a rare, rapidly‐progressing and aggressive variant of primary breast cancer. Depletion of LCN2 in IBC cell lines reduced colony formation, migration, and cancer stem cell populations in vitro and inhibited tumor growth, skin invasion, and brain metastasis in mouse models of IBC.

Background Inflammatory breast cancer (IBC) is a rare breast malignancy with poor outcomes compared with non-IBC. Age-related differences in tumor biology, treatment, and clinical outcomes have been described in non-IBC. This study evaluated age-related differences in IBC. Methods From an institutional prospective database, patients with an IBC diagnosed from 2010 to 2019 were identified. Age was categorized as 40 years or younger, 41 to 64 years, and 65 years or older. Demographics, clinicopathologic features, and treatment received were compared. Recurrence and survival outcomes were analyzed using the log-rank test and the Cox proportional hazards model. Results Of 523 IBC patients, 113 (21.6%) were age 40 years or younger, and 72 (13.8%) were age 65 years or older. The groups did not differ statistically by race/ethnicity, N stage, clinical stage, or tumor subtype. The younger patients included a higher proportion of Hispanic and Asian patients, triple-negative breast cancer (TNBC), and clinical N2/N3. Trimodality therapy was received by 92% of the stage 3 patients, with no difference in pathologic complete response (pCR) by age (23.3% vs 28.6%; p = 0.46). During a median follow-up period of 40 months, 17% of the patients experienced locoregional recurrence and 42.8% had distant metastasis. No difference in 3-year recurrence-free survival (57.9% vs 42.6% vs 54%; p = 0.42, log rank) or overall survival (OS) (75.6% vs 77.1% vs 64.4%; p = 0.31, log rank) by age was observed, and no difference in OS by age in de novo stage 4 disease was observed. In the multivariate analysis, worse OS was associated with TNBC (hazard ratio [HR], 1.99, 95% confidence interval [CI], 1.31-3.05) and no pCR (HR, 4.45; 95% CI, 2.16-9.18). Conclusion No significant differences were observed in demographics, treatment patterns, or clinical outcomes for IBC patients age 40 years or younger compared with those age 65 years or older treated by a specialized multidisciplinary team. These findings do not support age-related treatment de-escalation in IBC.

Nearly one-third of patients with inflammatory breast cancer (IBC) present with de novo stage IV disease. There are limited data on frequency and clinical outcomes of contralateral axillary metastasis (CAM) in IBC with no consensus diagnostic and treatment guidelines. Frequency of synchronous CAM was calculated in unilateral IBC patients at a single center (10/2004–6/2019). Clinicopathologic variables, diagnostic evaluation, treatment received, and overall survival (OS) were assessed and compared. Of 588 unilateral IBC patients, 49 (8.3%) had synchronous CAM. Of these, 32 (65.3%) also presented with metastatic disease at another distant site. CAM was not associated with age, tumor laterality, breast cancer subtype, grade, or cN stage (p > 0.05). The sensitivity/specificity to detect CAM was as follows: mammography (18.2%/99.2%), ultrasound (92.3%/95.5%), PET (90.1/99.1%), and MRI (76.0%/98.6%). Following systemic therapy, 22 patients had contralateral axillary surgery, and 18 received adjuvant contralateral nodal radiation. On multivariable analysis including tumor receptor subtypes, patients with stage IV-isolated CAM has statistically similar survival to stage III patients (HR 1.37, 95% CI 0.70–2.69, p = 0.36). Patients with Stage IV non-CAM (HR 2.18, 95% CI 1.66–2.85, p < 0.001) and stage IV-CAM plus other distant metastasis (HR 2.57, 95% CI 1.59–4.16, p < 0.001) had higher risk of death (reference: stage III disease). CAM in IBC was diagnosed in 8.3% of patients at presentation and was best identified by ultrasound and PET. We recommend routine contralateral axillary ultrasound as part of staging for all IBC patients. Diagnosis of CAM is a key first step toward much-needed prospective clinical trials evaluating management and outcomes of CAM in IBC.

Background: Triple-negative inflammatory breast cancer (TN-IBC) is the most aggressive breast cancer. It is important to identify its unique genetic and molecular features. In this study we performed comprehensive genomic and transcriptomic analyses of TN-IBC patient samples and identified TN-IBC unique features. Methods: We collected matched pretreatment blood and tumor samples from 19 patients with primary TN-IBC enrolled in a phase II clinical trial (NCT01036087). Patients were treated with neoadjuvant chemotherapy (NAC) or the anti-EGFR antibody panitumumab (PmAb) plus NAC (PmAb/NAC). Whole-exome sequencing, RNA sequencing, and multiplexed immunofluorescent staining were used to compare genetic and molecular profiles of these TN-IBC samples with 60 similarly analyzed stage III TN-non-IBC patient samples. We also compared the genetic and molecular characteristics of TN-IBC in patients who had a pathologic complete response (pCR) to NAC or PmAb/NAC treatment, a suitable surrogate end point for IBC, with those who did not have pCR (non-pCR). Results: Most TN-IBC patients (90%) had somatic gene alterations, most frequently in TP53 (42%), GATA3 (37%), and PI3KCA (26%). TN-IBC had distinct molecular and cellular differences from TN-non-IBC: a higher frequency of alteration of GATA3 (adj-p=0.001), KEAP1 (adj-p=0.05), CDKN1B (adj-p=0.05), amplification of ARNT, DDR2, BCL9, LMNA, and NDRG1, lower mutation load, and fewer copy number variations (p Conclusion: Our study demonstrated distinct genetic abnormalities, immune responses, and molecular characteristics associated with TN-IBC as well as differences related to patients’ responses to NAC and PmAb/NAC. This first comprehensive genomic, transcriptomic, and immune profiling of the largest TN-IBC patient cohort improves our understanding of the molecular landscape of the most aggressive subtype of breast cancer. Our analysis could lead to the discovery of novel prognostic biomarkers and druggable targets for TN-IBC. Citation Format: Xiaoping Wang, Li Zhao, Takashi Semba, Xingzhi Song, Mark Knafl, Savitri Krishnamurthy, Shan Shao, Larry W. Coffer II, Angela Alexander, Anita Wood, Swetha Bopparaju, Wendy A. Woodward, Randy Chu, Jianhua Zhang, Scott Woodman, Andrew Futreal, Clinton Yam, Debu Tripathy, Naoto T. Ueno. Genomic and transcriptomic analyses identify distinct features of triple-negative inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1395.

The role of modified radical mastectomy (MRM) in patients with de novo stage IV inflammatory breast cancer (IBC) remains controversial. We evaluated the impact of MRM on outcomes in this population. Ninety-seven women presenting with stage IV IBC were identified in an institutional database (2007–2016) and were stratified by receipt of MRM or no surgery (non-MRM). Demographic, clinicopathologic, and treatment factors were compared. Local–regional recurrence patterns were described and survival analyses were conducted. All patients initially received chemotherapy. Fifty-two patients (53.6%) underwent MRM; 47 received post-mastectomy radiation. Differences between the non-MRM and MRM groups included tumor receptor subtypes (hormone receptor-positive [HR+]/human epidermal growth factor receptor 2-positive [HER2+]: 4.4% vs. 19.2%; HR+/HER2-negative [HER2−]: 31.1% vs. 44.2%; HR-negative [HR−]/HER2+: 24.4% vs. 15.4%; and HR−/HER2−: 40.0% vs. 21.2%; p = 0.03), number of metastatic sites (3 vs. 2; p = 0.01), and clinical partial/complete response to chemotherapy (13.3% vs. 75.0%; p

Post-mastectomy radiation therapy (PMRT) in women with pathologic stage T1-2N1M0 breast cancer is controversial.Data from five North American institutions including women undergoing mastectomy without neoadjuvant therapy with pT1-2N1M0 breast cancer treated from 2006 to 2015 were pooled for analysis. Competing-risks regression was performed to identify factors associated with locoregional recurrence (LRR), distant metastasis (DM), overall recurrence (OR), and breast cancer mortality (BCM).A total of 3532 patients were included for analysis with a median follow-up time among survivors of 6.8 years (interquartile range [IQR], 4.5-9.5 years). The 2154 (61%) patients who received PMRT had significantly more adverse risk factors than those patients not receiving PMRT: younger age, larger tumors, more positive lymph nodes, lymphovascular invasion, extracapsular extension, and positive margins (p .05 for all). On competing risk regression analysis, receipt of PMRT was significantly associated with a decreased risk of LRR (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.14-0.31; p .001) and OR (HR, 0.76; 95% CI, 0.62-0.94; p = .011). Model performance metrics for each end point showed good discrimination and calibration. An online prediction model to estimate predicted risks for each outcome based on individual patient and tumor characteristics was created from the model.In a large multi-institutional cohort of patients, PMRT for T1-2N1 breast cancer was associated with a significant reduction in locoregional and overall recurrence after accounting for known prognostic factors. An online calculator was developed to aid in personalized decision-making regarding PMRT in this population.

Purpose Mild breast cancer-related lymphedema (BCRL) is clinically diagnosed as a 5%–10% increase in arm volume, typically measured no earlier than 3–6 months after locoregional treatment. Early BCRL treatment is associated with better outcomes, yet amid increasing evidence that lymphedema exists in a latent form, treatment is typically delayed until arm swelling is obvious. In this study, we investigated whether near-infrared fluorescence lymphatic imaging (NIRF-LI) surveillance could characterize early onset of peripheral lymphatic dysfunction as a predictor of BCRL. Methods In a prospective, longitudinal cohort/observational study (NCT02949726), subjects with locally advanced breast cancer who received axillary lymph node dissection and regional nodal radiotherapy (RT) were followed serially, between 2016 and 2021, before surgery, 4–8 weeks after surgery, and 6, 12, and 18 months after RT. Arm volume was measured by perometry, and lymphatic (dys) function was assessed by NIRF-LI. Results By 18 months after RT, 30 of 42 study subjects (71%) developed mild–moderate BCRL (i.e., ≥ 5% arm swelling relative to baseline), all manifested by “dermal backflow” of lymph into lymphatic capillaries or interstitial spaces. Dermal backflow had an 83% positive predictive value and 86% negative predictive value for BCRL, with a sensitivity of 97%, specificity of 50%, accuracy of 83%, positive likelihood ratio of 1.93, negative likelihood ratio of 0.07, and odds ratio of 29.00. Dermal backflow appeared on average 8.3 months, but up to 23 months, before the onset of mild BCRL. Conclusion BCRL can be predicted by dermal backflow, which often appears months before arm swelling, enabling early treatment before the onset of edema and irreversible tissue changes.

Introduction: The first high-quality clinical trial to support ultrahypofractionated whole-breast irradiation (ultra-HF-WBI) for invasive early-stage breast cancer (ESBC) was published in April 2020, coinciding with the beginning of the COVID-19 pandemic. We analyzed adoption of ultra-HF-WBI for ductal carcinoma in situ (DCIS) and ESBC at our institution after primary trial publication. Methods and Materials: We evaluated radiation fractionation prescriptions for all patients with DCIS or ESBC treated with WBI from March 2020 to May 2021 at our main campus and regional campuses. Demographic and clinical characteristics were extracted from the electronic medical record. Treating physician characteristics were collected from licensure data. Hierarchical logistic regression models identified factors correlated with adoption of ultra-HF-WBI (26 Gy in 5 daily factions [UK-FAST-FORWARD] or 28.5 Gy in 5 weekly fractions [UK-FAST]). Results: Of 665 included patients, the median age was 61.5 years, and 478 patients (71.9%) had invasive, hormone-receptor-positive breast cancer. Twenty-one physicians treated the included patients. In total, 249 patients (37.4%) received ultra-HF-WBI, increasing from 4.3% (2 of 46) in March-April 2020 to a high of 45.5% (45 of 99) in July-August 2020 (P < .001). Patient factors associated with increased use of ultra-HF-WBI included older age (≥50 years old), low-grade WBI without inclusion of the low axilla, no radiation boost, and farther travel distance (P < .03). Physician variation accounted for 21.7% of variance in the outcome, with rate of use of ultra-HF-WBI by the treating physicians ranging from 0% to 75.6%. No measured physician characteristics were associated with use of ultra-HF-WBI. Conclusions: Adoption of ultra-HF-WBI at our institution increased substantially after the publication of randomized evidence supporting its use. Ultra-HF-WBI was preferentially used in patients with lower risk disease, suggesting careful selection for this new approach while long-term data are maturing. Substantial physician-level variation may reflect a lack of consensus on the evidentiary standards required to change practice.

Purpose On June 13 to 14, 2019, the American Society for Radiation Oncology and the Radiological Society of North America convened a workshop on the treatment of oligometastatic disease in Washington, DC. The workshop was initiated for several reasons. First, oligometastatic disease is of increasing academic and community interest and has been identified by the American Society for Radiation Oncology membership as a top research priority. Second, emerging imaging and diagnostic technologies are more readily defining and detecting oligometastatic disease, making contemporary discussion of oligometastatic disease especially relevant. Third, radiosurgery and radiation in general are theorized to be ideal noninvasive therapy for the treatment of oligometastatic disease. Finally, innovations in targeted therapy and immune therapy have the potential to reverse widely disseminating disease into an oligometastatic state. Methods and Materials The workshop was organized into 2 keynote addresses, 6 scientific sessions, and 3 group discussions during an end-of-workshop breakout session. New scientific work was presented in the form of 4 oral presentations and a poster session. Workshop participants were charged with attempting to answer 3 critical questions: (1) Can we refine the clinical and biological definitions of oligometastatic disease; (2) how can we better treat oligometastatic disease; and (3) what clinical trials are needed? Results Here, we present the proceedings of the workshop. Conclusions The clinical implications of improved treatment of oligometastatic disease are enormous and immediate. Radiation oncology and diagnostic radiology should rightly be at the forefront of the characterization and treatment of oligometastatic disease. Focused effort is required so that we can translate current efforts of large numbers of studies with few patients to larger studies of larger impact.

Purpose To evaluate burnout in an academic radiation oncology program after the workforce shifted to working from home all or part of the time to better understand the impact of remote work and if it is sustainable after the COVID-19 virus abates. Methods and Materials In May 2020, in the midst of work-safe policies in the state and stabilizing COVID-19 case numbers, the Qualtrics-based MiniZ burnout survey was amended to include questions related to COVID-19 and working from home and was emailed to all radiation oncology employees across 3 departments: radiation oncology, radiation physics, and experimental radiation oncology. Descriptive and χ2 statistics were calculated within Qualtrics using StatIQ to evaluate factors associated with burnout and positive work from home experience. Results Five hundred seventy-five employees completed the survey. Aggregating 3 responses that indicate having some degree of burnout, the rate of burnout across the cohort was 32%. For the same survey questions administered a year earlier, burnout rate was reported to be 40%. In the current survey, radiation oncology faculty and therapists had the highest reported burnout rates, at 47% and 44%, respectively (P = .031). The majority of employees working from home at least part of the time reported the experience was positive (74%, 323/436), and feeling positive about working from home was associated with reduced burnout (P = .030). Qualitative data review suggested the main drivers of unfavorable work-from-home responses were child/family care issues and information technology issues. Conclusions Burnout was not increased during the emerging COVID-19 period compared with pre-COVID data. The shift to working from home was positive for most of the workforce and a potential benefit in reducing burnout for many staff groups. Maintaining work-from-home options post COVID-19 may help reduce burnout long term. It is important to personalize options for those unable to work effectively from home and to resolve information technology challenges to ensure functionality.

Modified radical mastectomy (MRM), which includes axillary dissection, is the standard of care for inflammatory breast cancer (IBC). While more limited axillary staging after neoadjuvant chemotherapy (NAC) in clinically node-positive non-IBC has been increasingly adopted, the impact of these techniques in IBC is not clear. To inform patient selection for further study of limited axillary surgery, we aimed to describe the frequency and factors associated with pathological node-negativity (ypN0) in IBC. Patients with IBC who received NAC and MRM were identified from a prospective institutional database (2004–2019). Binary logistic regression analyses were conducted to identify factors associated with ypN0. Of 453 patients, 189 (41.7%) had a post-NAC clinical nodal stage (ycN stage) of N0 (ycN1: 150, 33.1%; ycN2: 4, 0.9%; ycN3: 47, 10.4%; unknown: 63, 13.9%); 156 (34%) were ypN0. On multivariable analysis, higher tumor grade was not associated with ypN0 (odds ratio [OR] 1.59, 95% confidence interval [CI] 0.90–2.81, p =0.11). Compared with hormone receptor (HR)-negative/human epidermal growth factor receptor 2 (HER2)-negative tumors (n =113, 24.9%), HR-positive/HER2-negative tumors (n =169, 37.3%) had a trend toward less ypN0 (OR 0.55, 95% CI 0.29–1.02, p =0.06); HR-positive/HER2-positive tumors (n =79, 17.4%) were similar to HR-negative/HER2-negative tumors (OR 0.72, 95% CI 0.35–1.48, p =0.37); and HR-negative/HER2-positive tumors (n =92, 20.3%) were associated with increased ypN0 (OR 4.82, 95% CI 2.41–9.63, p

During the coronavirus disease 2019 pandemic, minimizing exposure risk for patients with cancer and health care personnel was of utmost importance. Here, we present steps taken to date to flatten the curve at the radiation oncology division of a tertiary cancer center with the goal of mitigating risk of exposure among patients and staff, and optimizing resource utilization. Response to the coronavirus disease 2019 pandemic in this large tertiary referral center included volume reduction, personal protective equipment recommendations, flexible clinic visit interaction types dictated by need and risk reduction, and numerous social distancing strategies. We hope these outlined considerations can assist the wider radiation oncology community as we collectively face this ongoing challenge.

Spurred by the lack of progress in improving outcomes in patients with inflammatory breast cancer (IBC), a deadly and aggressive type of breast cancer, Susan G. Komen, the Inflammatory Breast Cancer Research Foundation, and the Milburn Foundation convened patient advocates, breast cancer researchers, and clinicians to review the state of IBC care and research globally, and propose specific initiatives to move the field forward. The outcome of the discussions was abundantly clear: the field needs a formal definition of IBC. Without a clear definition, both patient care and research suffer. Diagnosis remains subjective and treatment variable. Clinical trials become inherently underpowered by inclusion of subjects with locally advanced, but not inflammatory, breast cancer. Similarly, the search for a molecular sine qua non or unifying pathway aberration is hindered by inclusion of bio-specimens from subjects with a different disease. The goal is to move beyond the subjective ‘clinical diagnosis’ to a set of specific diagnostic criteria and scoring system that will advance IBC research and facilitate the discoveries that will improve care of IBC patients. Here we propose a definition of IBC, based on a review of clinical, and pathologic features. Table 1. Proposed Scoring System for inflammatory breast cancer diagnosisPriority FactorCharacteristicScore3213Timing of signs/symptoms≤ 3 months3-6 months> 6 months3Skin changesPeau d’orangeSkin edema/thickening (≥ 1/3 of the breast)Focal skin edema/thickening (< 1/3 of the breast)3Swelling/engorgement of the breastClinically apparent enlargement of the breast or new asymmetry in breast sizeBreast edema identified on imaging but not clinically detectable2Erythema or other skin discoloration: pink, red, darkened, bruising/purplish or serpiginous in characterNearly complete involvement of the breastPartial involvement of the breastMinimal involvement or ambiguous color change2Nipple abnormalitiesNew nipple inversionNew nipple flattening or other asymmetryCrusting of the nipple/areola without other nipple changes2Lymphatic emboliDermal lymphatic emboli present without evidence of direct involvement of the dermis or epidermisNon-dermal lymphatic embolic present in breast parenchyma or stroma1Breast imagingDiffuse involvement of breast parenchyma, with or without dominant massEnlargement of non-axillary nodes (internal mammary, supraclavicular, subpectoral etc.) With increased awareness of IBC, patients are coming to medical attention earlier when clinical characteristics may not be as profound as historically depicted. Not all criterion are required for a diagnosis. To determine the total score, multiply the priority factor by the score for each criteria, then add the subtotals for each criteria. A priority factor is used to weigh criterion more heavily that are key to a consistent diagnosis of IBC to better define breast cancers that are ambiguous. While we cannot currently recommend a molecular-genetic profile that unambiguously identifies IBC, we will also provide a panel of prioritized biomarkers that are strongly associated with IBC and deserve further study in cohorts meeting our diagnostic criteria. We acknowledge that our proposed scoring system requires validation and refinement. If accurate, we expect patients with IBC based on these criteria to have a different clinical course and outcome compared to patients with “non-inflammatory” locally advanced breast cancer (LABC). Ultimately, we envision using the final disease classification and scoring system to develop a staging system specific to IBC. The discovery and validation of a distinct molecular or genetic profile that identifies IBC is of utmost importance to advancing research in this disease and cannot be accomplished without a clear and validated definition of IBC. Citation Format: Ginny Mason, Beth A Overmoyer, Wendy A. Woodward, Sunil Badve, Robert J. Schneider, Reshma Jagsi, Julie E. Lang, Mary Alpaugh, Krissa Smith, Kathy Miller. Inflammatory breast cancer (IBC) defined: Proposed common diagnostic criteria and scoring - Moving beyond the subjective ‘clinical diagnosis’ of IBC to advance research [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 P6-15-03.

Introduction/Motivation: We previously reported IBC patients with limited breast-feeding history have a worse prognosis than those with greater breast feeding history. Further, we reported pregnancy related factors including multiple early pregnancies and not breast feeding as well as obesity are risk factors for triple negative and ER+ subtypes. Significant evidence suggests the microenvironment drives IBC symptoms and growth pattern. We sought to characterize the impact of purported risk factors on tumor growth, IBC-like skin symptoms and mammary gland microenvironment in animal models. Methods: We commissioned breeding of nulliparous, multiparous (x 2) force weaned, and multiparous naturally weaned (labeled nursing) mice. Mice in each of the three groups were fed either a low fat (10 Kcal %) or high fat (60 Kcal %) diet for three weeks before tumor cell injections. SUM 149 GFP Luc were injected into the left ventral #4 mammary fat pad. Mice were sacrificed, scored for the IBC-like symptom of gross skin invasion or evident skin symptoms, and tissue from the contralateral mammary gland were sectioned and stained with H and E. Analysis was performed on the 31 animals that developed primary tumors and were scored for skin invasion at the time of resection. Of these 26 mice had contralateral gland tissue assessed by H and E. Phenotypes including duct dilation, degree of adipose tissue, duct density, inflammation and necrosis were scored manually, 1-3 scale. Quadratic mixed models with random intercept were fitted to compare tumor growth. Fisher’s exact test and T-tests were performed to compare variables. Results: Tumor incidence and latency were not different by risk factor group. Tumor growth was faster in multiparous force weaned versus others, P < 0.0001, but unchanged by diet, P = 0.187. Force weaned animals on a high fat diet had a trend for increased skin invasion compared to others (force weaned high fat diet vs. other 85% vs. 42%; P = 0.08) suggesting a synergy for this IBC-like symptom. Contralateral gland ductal density (less dense) and ductal dilation (not dilated) were normal histologic variables which correlated with skin invasion on the tumor side (P =0.006 and P = 0.011, respectively). Gland density but not dilated ducts trended to correlation with force weaning, P = 0.07, but not diet. Discussion: In this effect size finding pilot study, combined risk factors were associated with a higher incidence of skin invasion of SUM149 xenografts. Changes in the microenvironment in the contralateral gland typical of involution were significantly associated with skin invasion, and gland density trends towards association with force weaning. These data provide provocative pilot results linking histologic effects in the microenvironment to tumor growth characteristics and support the hypothesis that involution induced by forced weaning may facilitate IBC-like tumor growth. These studies facilitate well-powered additional work to establish mechanism and automate normal tissue evaluation. Citation Format: Wintana Balema, Richard Larson, Renae Van Whye, Rong Ye, Jing Ning, Omar Rahal, Shane Stecklein, Savitri Krishnamurthy, Randa El-Zein, Wendy Woodward. Modeling limited breastfeeding and diet on IBC like tumor progression [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 P6-15-04.

Background: Inflammatory breast cancer (IBC) is an aggressive, locally advanced breast cancer with a poor prognosis including a median survival of less than 4 years and a 5-year survival rate of around 60-70%. Symptom monitoring and management has demonstrated improved cancer patient outcomes, including quality of life, resource utilization, ability to continue treatment, and disease-free survival. The use of disease-specific patient-reported outcomes (PROs) is critical for facilitating individualized symptom monitoring and management. While women with IBC likely experience significant and variable symptom burden from diagnosis through treatment and survivorship that may remain under-reported and unmanaged, there is limited description of the symptom burden in this population and no disease-specific valid and reliable instrument for measuring symptom burden in IBC. In addition, because the diagnosis of IBC is based on clinical criteria as opposed to molecular or pathological diagnostic criteria, attention to defining the disease-related symptoms may assist clinicians in making timely and accurate diagnoses. The purpose of this study was to describe the patient experience of IBC and define the content domain for a PRO measure of IBC symptom burden, using patient input to ensure content validity. Methods: This descriptive study is the first stage in development of a PRO IBC symptom burden measure. Twenty patients with IBC across the disease continuum described their experience in single qualitative interviews. Content analysis was used to describe their experience and define the symptom burden content domain. Results: Mean patient age was 52.8 years (range, 30-73 years); 50% with locally advanced and 50% with metastatic disease, with 85% receiving treatment at the time of the interview. Content analysis found 51 symptoms related to both disease and treatment, with 24 symptoms reported at least 20% of participants. Participants reported, on average, 13.1 symptoms (range, 3-23 symptoms). All participants described localized disease-related symptoms that were present at diagnosis, which included breast rash (40% of participants), changes in the texture of the breast (55%), nipple changes (25%), breast pain (40%), breast discoloration (70%), breast lump (55%), breast warmth (10%), and breast swelling (50%). Treatment-related symptoms varied among participants based on modalities received. Patients volunteered ways in which symptoms impacted daily activities and relationships and how symptoms were managed. Conclusions: We have completed our pilot study. Patients with IBC experience numerous symptoms related to disease and treatment, including many localized disease-related symptoms with various treatments resulting in unique symptom burden. Symptoms may result in interference with daily activities, relationships, life plans, treatment adherence, and mood. Well-designed PROs are essential for accurate symptom assessment and management to maintain patient functioning. The content domain for a PRO symptom-burden measure of IBC encompasses the severity and activity interference of common symptoms of IBC and its treatment. Citation Format: Meagan Whisenant, Angela Alexander, Loretta A. Williams, Wendy Woodward, Randa El-Zein, Naoto Tada Ueno. Establishing the content domain for a patient-reported outcomes measure to evaluate the unique symptom burden of inflammatory breast cancer [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 P6-15-06.

Inflammatory breast cancer (IBC) is an aggressive disease for which the spectrum of preclinical models was rather limited in the past. More recently, novel cell lines and xenografts have been developed. This study evaluates the transcriptome of an extended series of IBC preclinical models and performed a comparative analysis with patient samples to determine the extent to which the current models recapitulate the molecular characteristics of IBC observed clinically. We demonstrate that the IBC preclinical models are exclusively estrogen receptor (ER)-negative and of the basal-like subtype, which reflects to some extent the predominance of these subtypes in patient samples. The IBC-specific 79-signature we previously reported was retrained and discriminated between IBC and non-IBC preclinical models, but with a relatively high rate of false positive predictions. Further analyses of gene expression profiles revealed important roles for cell proliferation, MYC transcriptional activity, and TNFɑ/NFκB in the biology of IBC. Patterns of MYC expression and transcriptional activity were further explored in patient samples, which revealed interactions with ESR1 expression that are contrasting in IBC and nIBC and notable given the comparatively poor outcomes of ER+ IBC. Our analyses also suggest important roles for NMYC, MXD3, MAX, and MLX in shaping MYC signaling in IBC. Overall, we demonstrate that the IBC preclinical models can be used to unravel cancer cell intrinsic molecular features, and thus constitute valuable research tools. Nevertheless, the current lack of ER-positive IBC models remains a major hurdle, particularly since interactions with the ER pathway appear to be relevant for IBC.

This review highlights the considerations of the radiation oncologist when managing patients with inflammatory breast cancer (IBC) as well as the radiation oncologist's role as a member of the multi-disciplinary team.IBC makes up only 1-4% of all breast cancer diagnoses but incidence is increasing. IBC is diagnosed based on a constellation of clinical features, including the rapid onset of breast erythema and edema (peau d'orange) of one-third or more of the skin of the breast and with a palpable border to the edema. Most published IBC local-regional control rates are consistently lower than those observed in non-IBC, which the highlights the need for deliberate treatment techniques to maximize clinical outcomes.For this narrative review, we discuss the principles of radiation target delineation and dose escalation; highlight new findings in the local-regional management of IBC; provide a critical evaluation of the recent literature evaluating local-regional treatment of IBC; and offer a brief introduction to possible future directions regarding the optimal treatment and management of IBC based on our institutional experience.IBC is an aggressive type of breast cancer that warrants multi-disciplinary care from breast surgical, medical, and radiation oncology. Several strategies exist to enhance the effect of radiation therapy (RT) on local-regional control, including hyperfractionation, use of bolus, increased total RT dose, and radiosensitizers, which are currently being tested in randomized trials. With an individualized patient approach, local-regional control rates are improving for IBC.

Purpose Multigene panel testing has increased the detection of germline mutations in patients with breast cancer. The implications of using radiation therapy (RT) to treat patients with pathogenic variant (PV) mutations are not well understood and have been studied mostly in women with only BRCA1 or BRCA2 PVs. We analyzed oncologic outcomes and toxicity after adjuvant RT in a contemporary, diverse cohort of patients with breast cancer who underwent genetic panel testing. Methods and Materials We retrospectively reviewed the records of 286 women with clinical stage I-III breast cancer diagnosed from 1995 to 2017 who underwent surgery, breast or chest wall RT with or without regional nodal irradiation, multigene panel testing, and evaluation at a large cancer center's genetic screening program. We evaluated rates of overall survival, locoregional recurrence, disease-specific death, and radiation-related toxicities in 3 groups: BRCA1/2 PV carriers, non-BRCA1/2 PV carriers, and patients without PV mutations. Results PVs were detected in 25.2% of the cohort (12.6% BRCA1/2 and 12.6% non-BRCA1/2). The most commonly detected non-BRCA1/2 mutated genes were ATM, CHEK2, PALB2, CDH1, TP53, and PTEN. The median follow-up time for the entire cohort was 4.4 years (95% confidence interval, 3.8-4.9 years). No differences were found in overall survival, locoregional recurrence, or disease-specific death between groups (P > .1 for all). Acute and late toxicities were comparable across groups. Conclusion Oncologic and toxicity outcomes after RT in women with PV germline mutations detected by multigene pane testing are similar to those in patients without detectable mutations, supporting the use of adjuvant RT as a standard of care when indicated.

PURPOSE To our knowledge, NRG/RTOG 9804 is the only randomized trial to assess the impact of whole breast irradiation (radiation therapy [RT]) versus observation (OBS) in women with good-risk ductal carcinoma in situ (DCIS), following lumpectomy. Long-term results focusing on ipsilateral breast recurrence (IBR), the primary outcome, are presented here. PATIENTS AND METHODS Eligible patients underwent lumpectomy for DCIS that was mammogram detected, size ≤ 2.5 cm, final margins ≥ 3 mm, and low or intermediate nuclear grade. Consented patients were randomly assigned to RT or OBS. Tamoxifen use was optional. Cumulative incidence was used to estimate IBR, log-rank test and Gray's test to compare treatments, and Fine-Gray regression for hazard ratios (HRs). RESULTS A total of six hundred thirty-six women were randomly assigned from 1999 to 2006. Median age was 58 years and mean pathologic DCIS size was 0.60 cm. Intention to use tamoxifen was balanced between arms (69%); however, actual receipt of tamoxifen varied, 58% RT versus 66% OBS ( P = .05). At 13.9 years' median follow-up, the 15-year cumulative incidence of IBR was 7.1% (95% CI, 4.0 to 11.5) with RT versus 15.1% (95% CI, 10.8 to 20.2) OBS ( P = .0007; HR = 0.36; 95% CI, 0.20 to 0.66); and for invasive LR was 5.4% (95% CI, 2.7 to 9.5) RT versus 9.5% (95% CI, 6.0 to 13.9) OBS ( P = .027; HR = 0.44; 95% CI, 0.21 to 0.91). On multivariable analysis, only RT (HR = 0.34; 95% CI, 0.19 to 0.64; P = .0007) and tamoxifen use (HR = 0.45; 95% CI, 0.25 to 0.78; P = .0047) were associated with reduced IBR. CONCLUSION RT significantly reduced all and invasive IBR for good-risk DCIS with durable results at 15 years. These results are not an absolute indication for RT but rather should inform shared patient-physician treatment decisions about ipsilateral breast risk reduction in the long term following lumpectomy.

Background Previous studies have examined the association of statin therapy and breast cancer outcomes with mixed results. The objective of this study was to investigate the clinical effects of incident statin use among individuals with triple-negative breast cancer (TNBC). Methods Data from the Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry-Medicare databases were used, and women aged ≥66 years who had stage I, II, and III breast cancer were identified. Multivariable Cox proportional hazards regression models were used to examine the association of new statin use in the 12 months after a breast cancer diagnosis with overall survival (OS) and breast cancer-specific survival (BCSS). Results When examining incident statin use, defined as the initiation of statin therapy in the 12 months after breast cancer diagnosis, a significant association was observed between statin use and improved BCSS (standardized hazard ratio, 0.42; 95% confidence interval [CI], 0.20-0.88; P = .022) and OS (hazard ratio, 0.70; 95% CI, 0.50-0.99; P = .046) among patients with TNBC (n = 1534). No association was observed with BCSS (standardized hazard ratio, 0.99; 95% CI, 0.71-1.39; P = .97) or OS (hazard ratio, 1.04; 95% CI, 0.92-1.17; P = .55) among those without TNBC (n = 15,979). The results were consistent when examining statin exposure as a time-varying variable. Conclusions Among women with I, II, and III TNBC, initiation of statin therapy in the 12 months after breast cancer diagnosis was associated with an OS and BCSS benefit. Statins may have a role in select patients with breast cancer, and further investigation is warranted.

Background Inflammatory breast cancer (IBC) is a clinical diagnosis. Here, we examined the association of a “classic” triad of clinical signs, swollen involved breast, nipple change, and diffuse skin change, with overall survival (OS). Method Breast medical photographs from patients enrolled on a prospective IBC registry were scored by two independent reviewers as classic (triad above), not classic, and difficult to assign. Chi‐squared test, Fisher's exact test, and Wilcoxon rank‐sum test were used to assess differences between patient groups. Kaplan–Meier estimates and the log‐rank test and Cox proportional hazard regression were used to assess the OS. Results We analyzed 245 IBC patients with median age 54 (range 26–81), M0 versus M1 status (157 and 88 patients, respectively). The classic triad was significantly associated with smoking, post‐menopausal status, and metastatic disease at presentation (p = 0.002, 0.013, and 0.035, respectively). Ten‐year actuarial OS for not classic and difficult to assign were not significantly different and were grouped for further analyses. Ten‐year OS was 29.7% among patients with the classic sign triad versus 57.2% for non‐classic (p, Inflammatory breast cancer (IBC) is a clinical diagnosis. Here, we examined the association of a “classic” triad of clinical signs, swollen involved breast, nipple change, and diffuse skin change, with overall survival (OS). Our study concluded for the first time that a triad of classic IBC signs independently predicted OS in patients diagnosed with IBC.

Male breast cancer treatment regimens are often extrapolated from female-based studies because of a paucity of literature analyzing male breast cancer. Using ClinicalTrials.gov, we analyzed breast cancer randomized clinical trials (RCTs) to determine which factors were associated with male-gender inclusion. Of 131 breast cancer RCTs identified, male patients represented 0.087% of the total study population, which is significantly less than the proportion of male patients with breast cancer in the U.S. (0.95%; p < .001). Twenty-seven trials included male patients (20.6%). Lower rates of male inclusion were seen in trials that randomized or mandated hormone therapy as part of the trial protocol compared with trials that did not randomize or mandate endocrine therapy (2.5% vs. 28.6% male inclusion; p < .001). It is imperative for breast cancer clinical trials to include men when allowable in order to improve generalizability and treatment decisions in male patients with breast cancer.

Metastasis is the main cause of cancer-related mortality. Despite intense efforts to understand the mechanisms underlying the metastatic process, treatment of metastatic cancer is still challenging. Here we describe a chemotherapy-induced, host-mediated mechanism that promotes remodeling of the extracellular matrix (ECM), ultimately facilitating cancer cell seeding and metastasis. Paclitaxel (PTX) chemotherapy enhanced rapid ECM remodeling and mechano-structural changes in the lungs of tumor-free mice, and the protein expression and activity of the ECM remodeling enzyme lysyl oxidase (LOX) increased in response to PTX. A chimeric mouse mode harboring genetic LOX depletion revealed chemotherapy-induced ECM remodeling was mediated by CD8+ T cells expressing LOX. Consistently, adoptive transfer of CD8+ T cells, but not CD4+ T cells or B cells, from PTX-treated mice to naïve immuno-deprived mice induced pulmonary ECM remodeling. Lastly, in a clinically relevant metastatic breast carcinoma model, LOX inhibition counteracted the metastasis-promoting, ECM-related effects of PTX. This study highlights the role of immune cells in regulating ECM and metastasis following chemotherapy, suggesting that inhibiting chemotherapy-induced ECM remodeling represents a potential therapeutic strategy for metastatic cancer.

Purpose Optimal treatment of patients diagnosed with de novo metastatic breast cancer limited to the mediastinum or sternum has never been delineated. Herein, we sought to determine the efficacy of multimodality treatment, including metastasis-directed radiation therapy, in curing patients with this presentation. Methods and Materials This is a single-institution retrospective cohort study of patients with de novo metastatic breast cancer treated from 2005 to 2014, with a 50-month median follow-up for the primary cohort. The primary patient cohort had metastasis limited to the mediastinum/sternum treated with curative intent (n = 35). We also included a cohort of patients with stage IIIC disease treated with curative intent (n = 244). Additional groups included a mediastinal/sternal palliative cohort (treatment did not include metastasis-directed radiation therapy; n = 14) and all other patients with de novo stage IV disease (palliative cohort; n = 1185). The primary study outcomes included locoregional recurrence-free survival (LRRFS), recurrence-free survival (RFS), and overall survival (OS), which were calculated using the Kaplan-Meier method. Cox multivariable models compared survival outcomes across treatment cohorts adjusted for molecular subtype, age, and race. Results For the mediastinal/sternal curative-intent cohort, 5-year LRRFS was 85%, RFS was 52%, and OS was 63%. After adjustment, there was no statistically significant difference in LRRFS (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.13-1.13; P = .08), RFS (HR, 0.87; 95% CI 0.50-1.49; P = .61), or OS (HR, 0.79; 95% CI 0.44-1.43; P = .44) between the stage IIIC cohort and the mediastinal/sternal curative-intent cohort (referent). In contrast, RFS was worse for the mediastinal/sternal palliative cohort (HR, 2.29; 95% CI 1.05-5.00; P = .04). OS was worst for the de novo stage IV palliative cohort (HR, 2.61; 95% CI 1.50-4.53; P Conclusions For select patients presenting with breast cancer metastatic to the sternum and/or mediastinum, curative-intent treatment with chemotherapy, surgery, and radiation yields outcomes similar to those of stage IIIC disease and superior to de novo stage IV breast cancer treated with palliative intent.

The development of cancer and their response to radiation are intricately linked to the tumor microenvironment (TME) in which they reside. Tumor cells, immune cells, and stromal cells interact with each other and are influenced by the microbiome and metabolic state of the host, and these interactions are constantly evolving. Stromal cells not only secrete extracellular matrix and participate in wound contraction, but they also secrete fibroblast growth factors(FGF) molecules, which mediate macrophage differentiation. Tumor-associated macrophages migrate to hypoxic areas and secrete vascular endothelial growth factor (VEGF) to promote angiogenesis. The microbiome and its byproducts alter the metabolic milieu by shifting the balance between glucose utilization and fatty acid oxidation, and these changes subsequently influence the immune response in the TME. Not only does radiation exert cell-autonomous effects on tumor cells, but it influences both the tumor-promoting and tumor-suppressive components in the TME. To gain a deeper understanding of how the TME influences the response to radiation, the American Society for Radiation Oncology and the American Association of Cancer Research organized a scientific workshop on July 26–27, 2018, to discuss how the microbiome, the immune response, the metabolome, and the stroma all shift the balance between radiosensitivity and radioresistance. The proceedings from this workshop are discussed here and highlight recent discoveries in the field, as well as the most important areas for future research.

PURPOSE: The carbohydrate Sialyl Lewis(X) (sLe(X)) mediates cell adhesion, is critical in the normal function of immune cells, and is frequently over-expressed on cancer cells. We assessed the association, differential levels, and prognostic value of sLe(X) and inflammatory cytokines/chemokines in breast cancer sera. METHODS: We retrospectively measured sLe(X) and a panel of cytokines/chemokines in the sera of 26 non-invasive ductal carcinoma in situ (DCIS), 154 invasive non-metastatic breast cancer (non-MBC), 63 metastatic breast cancer (MBC) patients, and 43 healthy controls. Differences in sLe(X) and inflammatory cytokines among and between patient groups and healthy controls were assessed with nonparametric tests and we performed survival analysis for the prognostic potential of sLe(X) using a cut-off of 8 U/ml as previously defined. RESULTS: Median serum sLe(X) was significantly higher than controls for invasive breast cancer patients (MBC and non-MBC) but not DCIS. In univariate analysis, we confirmed patients with serum sLe(X) >8 U/ml have a significantly shorter progression free survival (PFS) (P=0.0074) and overall survival (OS (P=0.0003). Similarly, patients with high serum MCP-1 and IP-10 had shorter OS (P=0.001 and P

OBJECTIVE: To prospectively characterize toxicity and cosmesis after accelerated partial breast irradiation (APBI) with 3D conformal radiotherapy (3D-CRT) or single-entry multilumen intracavitary brachytherapy. PATIENTS AND METHODS: Two hundred eighty-one patients with pTis, pT1N0, or pT2N0 (≤3.0 cm) breast cancer treated with segmental mastectomy were prospectively enrolled from December 2008 through August 2014. APBI was delivered using 3D-CRT (N=29) or with a SAVI® (N=176), Contura® (N=56), or MammoSite® (N=20) brachytherapy catheter. Patients were evaluated at protocol-specified intervals, at which time the radiation oncologist scored cosmetic outcome, toxicities, and recurrence status using a standardized template. RESULTS: Median follow-up is 41 months. Grade 1 seroma and fibrosis were more common with brachytherapy than with 3D-CRT (50.4% vs. 3.4% for seroma, P 5.1 mm, dose homogeneity index > 0.54, and volume of non-conformance ≤ 0.89 cc. Five-year ipsilateral breast recurrence was 4.3% for brachytherapy and 4.2% for 3D-CRT APBI patients (P=0.95). CONCLUSIONS: Brachytherapy APBI is associated with higher rates of grade 1 fibrosis and seroma than 3D-CRT but lower rates of grade 1 edema and grade 2–3 pain than 3D-CRT. Rates of radiation oncologist-reported “fair” or “poor” cosmetic outcome are higher with brachytherapy. We identified dosimetric parameters that predict reduced risk of adverse cosmetic outcome after brachytherapy-based APBI. Ipsilateral breast recurrence was equivalent for brachytherapy and 3D-CRT.

Background: Research on the prognostic or predictive value of Ki-67 among patients with inflammatory breast cancer (IBC) is limited. Methods: Using the comprehensive database of the Morgan Welch Inflammatory Breast Cancer Research Program at MD Anderson Cancer Center, we identified a cohort of breast cancer patients who were diagnosed with IBC between 1992 and 2012. Distributions of survival outcomes were estimated by the Kaplan-Meier method and compared by log-rank tests and Cox models. Results: Among a total of 257 patients with stage III IBC, the mean percentage of tumor cells that stained positive for Ki-67 was 48%, (range, 4% to 100%). Using a cutoff of 20% as being Ki-67 positive, this characteristic tended to be associated with worse overall survival (p=0.07) in the univariate analysis. After controlling for hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) status and having received trimodality treatment, the association between Ki-67 status and overall survival remained marginally significant (p=0.07). The effects of trimodality treatment on overall survival were statistically significantly different between patients with Ki-67-positive tumors (hazard ratio=0.26, 95% confidence interval [CI]=0.15-0.44, p

578 Background: Advances in radiotherapy allow the ability to deliver ablative treatments without compromising outcomes, but there has been limited application of these treatments to early-stage breast cancers. The purpose of this study was to explore patients’ interest in pursuing nonsurgical treatment approaches for their early-stage breast cancer. Methods: Investigators conducted a qualitative descriptive study involving semi-structured interviews with 21 early-stage breast cancer patients eligible for participation in a phase 2 trial offering omission of surgery. Interviews were transcribed, and three independent reviewers performed an inductive, thematic analysis to generate themes and subthemes. Results: Data analysis revealed the following factors that impacted patients’ willingness and desire to explore nonsurgical treatment options: Perceptions and feelings about their cancer; Current quality of life and the level of support available in their daily life; External conversations focusing on family members’ and friends’ experiences with cancer and/or cancer treatments; Personal healthcare experiences, including with their current breast cancer diagnosis; Perceptions and feelings about their physicians; Conversations with their physicians about their treatment options; and Self-identified desire to direct care decisions. Specifically, patients described fearing surgery and surgical recovery and wanting to avoid negative surgery-related events previously experienced by friends, family, and themselves. Participants also expressed a desire to preserve their breast(s), receive treatment per the latest research, match the level of treatment with the severity of their cancer, and avoid other comorbidities as reasons for omitting surgery. Patient reasons for pursuing surgery included the desire to remove their cancer immediately, prior positive experiences of friends, family, and themselves with surgery, lack of concern about preserving their breast(s), and prior negative experiences of friends, family, and themselves with radiation. Conclusions: The results of this study highlight that there is patient interest in nonsurgical options for biologically favorable early stage breast cancers. A key factor hindering patient education and awareness of nonsurgical options is how the physician frames the discussion and presents treatment options. In addition, patients’ self-identity and the prior experiences of friends, family, and self with cancer treatment and surgery in general appear to be key factors in their decision-making. The findings from this study demonstrate an unmet need to explore nonsurgical options for early-stage breast cancer. Study results can help shape conversations around shared decision making and clinical trial design and result in more personalized treatment options for women with early-stage breast cancer.

1007 Background: Prospective and retrospective studies of patients (pts) with oligometastatic (OM) disease have supported that metastases (mets) directed treatment (MDT) with SBRT or SR in addition to standard of care systemic therapy (SOC ST) can improve progression-free (PFS) and overall survival (OS) compared with SOC ST alone. However, randomized evidence in oligometastatic breast cancer (OMBC) are lacking. NRG-BR002, a randomized Phase IIR/III trial, sought to determine the efficacy of SOC ST + MDT (SBRT or SR) as first line treatment of OMBC. Methods: OMBC pts with ≤ 4 extracranial mets on standard imaging with controlled primary disease were eligible if on first line SOC ST for ≤ 12 months without progression. Pts were randomized (1:1) to ARM 1 – SOC ST (mainly chemotherapy, endocrine therapy, anti-HER2) or ARM 2 – SOC ST with MDT of all mets. Stratification included mets number (1 vs > 1), ER/PR and Her2 status, and chemotherapy use. Phase IIR targeted sample size was 128 total/116 eligible pts, for 92% power and 1-sided significance level = 0.15 to determine if adding MDT shows a signal for improved PFS (hazard ratio [HR] = 0.55, corresponding to median PFS (mPFS) from 10.5 to 19 months), in order to continue to the full phase III trial for OS. PFS and OS were estimated by Kaplan-Meier and arms compared with log-rank. Results: 125 of the 129 pts randomized were eligible (ARM 1 = 65, ARM 2 = 60). Key characteristics included median age 54, 79% ER+ or PR+/HER2-, 13% HER2+, 8% triple negative. 60% had 1 metastasis and 20% presented synchronously with primary disease. Following randomization, systemic therapy was delivered to 95% in ARM 1 and 93% in ARM 2; ablation: SBRT 93%, SR 2%, and 5% none. The median follow-up was 30 mo. The mPFS (70% CI) in ARM 1 was 23 mo (18, 29) and 19.5 mo (17, 36) in ARM 2; 24 and 36-mo PFS (70% CI) for ARM 1 were 45.7% (38.9, 52.5) and 32.8% (26.0, 39.5) compared with 46.8 (39.2, 54.3) and 38.1 (29.7, 46.6) in ARM 2; HR (70% CI): 0.92 (0.71, 1.17); and 1-sided log-rank p = 0.36. As PFS did not show signal, OS reporting is included: median OS was not reached in either arm; 36-mo OS (95% CI) in ARM 1 71.8% (58.9, 84.7) and ARM 2 68.9% (55.1, 82.6; 2-sided log-rank p = 0.54). Analysis of first failure showed new mets outside index area (Arm 1) /RT field (Arm 2) developed similarly in both arms at 40%. There were fewer new mets inside treated/index area for Arm 2 6.7% vs ARM 1 29.2%, respectively. There were no grade 5 treatment-related adverse events (AEs), 1 grade 4 AE in ARM 1, and 9.7% and 5.3% grade 3 AEs in ARMS 1 and 2, respectively. Circulating tumor cell counts (0 vs ≥1) at baseline were similar in both arms and were not prognostic HR (95% CI): 1.04 (0.54, 2.02). Conclusions: The addition of MDT to SOC ST did not show signal for improved PFS, nor OS difference in patients with OMBC. The trial will not proceed to the Phase III component. Clinical trial information: NCT02364557.

Purpose The adoption of hypofractionated whole-breast irradiation (HF-WBI) remains low, in part because of concerns regarding its safety when used with a tumor bed boost or in patients who have received chemotherapy or have large breast size. To address this, we conducted a randomized, multicenter trial to compare conventionally fractionated whole-breast irradiation (CF-WBI; 50 Gy/25 fx + 10 to 14 Gy/5 to 7 fx) with HF-WBI (42.56 Gy/16 fx + 10 to 12.5 Gy/4 to 5 fx). Patients and Methods From 2011 to 2014, 287 women with stage 0 to II breast cancer were randomly assigned to CF-WBI or HF-WBI, stratified by chemotherapy, margin status, cosmesis, and breast size. The trial was designed to test the hypothesis that HF-WBI is not inferior to CF-WBI with regard to the proportion of patients with adverse cosmetic outcome 3 years after radiation, assessed using the Breast Cancer Treatment Outcomes Scale. Secondary outcomes included photographically assessed cosmesis scored by a three-physician panel and local recurrence-free survival. Analyses were intention to treat. Results A total of 286 patients received the protocol-specified radiation dose, 30% received chemotherapy, and 36.9% had large breast size. Baseline characteristics were well balanced. Median follow-up was 4.1 years. Three-year adverse cosmetic outcome was 5.4% lower with HF-WBI ( Pnoninferiority = .002; absolute risks were 8.2% [n = 8] with HF-WBI v 13.6% [n = 15] with CF-WBI). For those treated with chemotherapy, adverse cosmetic outcome was higher by 4.1% (90% upper confidence limit, 15.0%) with HF-WBI than with CF-WBI; for large breast size, adverse cosmetic outcome was 18.6% lower (90% upper confidence limit, −8.0%) with HF-WBI. Poor or fair photographically assessed cosmesis was noted in 28.8% of CF-WBI patients and 35.4% of HF-WBI patients ( P = .31). Three-year local recurrence-free survival was 99% with both HF-WBI and CF-WBI ( P = .37). Conclusion Three years after WBI followed by a tumor bed boost, outcomes with hypofractionation and conventional fractionation are similar. Tumor bed boost, chemotherapy, and larger breast size do not seem to be strong contraindications to HF-WBI.

Patients with breast cancer and ipsilateral supraclavicular (SCV) node involvement at the time of diagnosis (TNM cN3c) have historically had poor outcomes. Radiation therapy (RT) has an important role because SCV nodes are not routinely surgically dissected. However, optimal locoregional management, contemporary outcomes, and prognostic factors are not well defined.We reviewed the data of patients with cN3c breast cancer treated at our institution between 2014 and 2019 with curative intent, including neoadjuvant chemotherapy, surgery, and adjuvant RT. All patients received comprehensive regional RT, including to the SCV nodes. Institutional guidelines recommend a 10-Gy or 16-Gy boost to resolved and unresolved N3 nodes, respectively. Overall survival (OS), recurrence-free survival (RFS), locoregional recurrence-free survival (LRRFS), and supraclavicular recurrence-free survival (SCRFS) were analyzed.Data from 173 consecutive patients were analyzed with a median follow-up time of 2.8 years. The median age was 54 years, 76 patients (44%) were estrogen receptor positive/human epidermal growth factor receptor 2 negative, 100 patients (58%) had T3/4 disease, and 10 patients (6%) underwent a neck dissection. In addition, 156 patients (90%) received a cumulative SCV dose of ≥60 Gy. The 5-year OS, SCRFS, LRRFS, and RFS rates were 73%, 95%, 86%, and 50%, respectively. The 5-year OS rate for a cumulative SCV dose of ≥60 Gy versus60 Gy was 75% versus 39% (P = .04). In the multivariable analysis, a cumulative SCV dose of ≥60 Gy, extranodal extension, receptor status, and Eastern Cooperative Oncology Group performance status were associated with OS. The 5-year SCRFS rates with and without neck dissection were 100% versus 95% (P = .57). Among patients with a postchemotherapy SCV node size of ≥1 cm without neck dissection, the 5-year SCRFS rate was 83%.In one of the largest series of patients with cN3c breast cancer, multimodality therapy using adjuvant RT with a SCV boost resulted in a 5-year LRRFS rate of 86%. There is a limited role for neck dissection as the 5-year SCRFS rate was 95% overall and 83% for residual SCV disease ≥1 cm after chemotherapy with RT alone. A cumulative SCV dose of ≥60 Gy was associated with improved OS, but not SCRFS, LRRFS, or RFS. A SCV boost should be considered in these patients as treatment was well-tolerated. Despite advances in systemic therapy, nearly half of patients developed distant metastases, highlighting the need for close observation after treatment.

Purpose To highlight the current evidence and the limitations in data to support a personalized approach in breast oncology radiation therapy management and define steps needed for clinical implementation. Methods and Materials A critical review of the current literature on the use of genomics in breast radiation therapy was undertaken by a group of breast radiation oncologists to discuss current data, future directions, and challenges. Results A summary of the existing data, ongoing clinical trials, and future directions is provided. The authors note many groups have developed radiation-specific genomic assays, which demonstrate promise in prediction of local control and benefit from radiation therapy; however, prospective validation of their utility is needed. Limitations continue to exist in our understanding of tumor biology and how it can be integrated into clinical practice. Conclusions Given the relative ubiquity of breast radiation therapy, the variety of dose and fractionation approaches, and the current data to support a personalized approach, it is our belief that the delivery of breast radiation therapy is uniquely poised for a genomically personalized radiation therapy approach. Prospective clinical trials implementing genomic signatures are needed at this time to advance the field.

Highlights • No unique genome signature or molecular therapy exists for inflammatory breast cancer (IBC), a highly aggressive breast cancer with a 5-year survival rate of less than 30%. • We show that various gene lists proposed as molecular footprints of IBC have no overlap and thus very limited predictive accuracy in identifying IBC samples. • We observed that single-sample gene set enrichment analysis (ssGSEA) of IBC samples along the epithelial-hybrid-mesenchymal spectrum can help IBC identification. • IBC samples robustly displayed a higher coefficient of variation in terms of EMT scores, as compared to non-IBC samples. • Higher heterogeneity along the epithelial-hybrid-mesenchymal spectrum can be regarded to be a hallmark of IBC and a possibly useful biomarker., Inflammatory breast cancer (IBC) is a highly aggressive breast cancer that metastasizes largely via tumor emboli, and has a 5-year survival rate of less than 30%. No unique genomic signature has yet been identified for IBC nor has any specific molecular therapeutic been developed to manage the disease. Thus, identifying gene expression signatures specific to IBC remains crucial. Here, we compare various gene lists that have been proposed as molecular footprints of IBC using different clinical samples as training and validation sets and using independent training algorithms, and determine their accuracy in identifying IBC samples in three independent datasets. We show that these gene lists have little to no mutual overlap, and have limited predictive accuracy in identifying IBC samples. Despite this inconsistency, single-sample gene set enrichment analysis (ssGSEA) of IBC samples correlate with their position on the epithelial-hybrid-mesenchymal spectrum. This positioning, together with ssGSEA scores, improves the accuracy of IBC identification across the three independent datasets. Finally, we observed that IBC samples robustly displayed a higher coefficient of variation in terms of EMT scores, as compared to non-IBC samples. Pending verification that this patient-to-patient variability extends to intratumor heterogeneity within a single patient, these results suggest that higher heterogeneity along the epithelial-hybrid-mesenchymal spectrum can be regarded to be a hallmark of IBC and a possibly useful biomarker.

Purpose/Objective(s) Patients with clinical N3b (cN3b) breast cancer often do not undergo surgical resection of gross internal mammary (IM) nodes. Therefore, radiation is important for curative therapy. However, limited data exist to guide treatment recommendations. Materials/Methods We retrospectively reviewed 119 patients with non-metastatic cN3b breast cancer treated at our institution between 2014 and 2019 with curative intent. Staging included u/s evaluation of all regional nodal basins. All patients received neoadjuvant chemotherapy (NAC), surgical resection of the breast primary and nodal dissection, followed by adjuvant radiation to the chest wall/breast, infraclavicular (ICV), SCV and IM nodes. Institutional nodal boost guidelines recommend 10 Gy to radiographically resolved N3b nodal basins, and 16 Gy to unresolved N3b nodes, normal tissue constraints permitting. Patient, tumor, and treatment characteristics were collected and analyzed using a saturated multivariable analysis (MVA) model with backwards elimination to identify variables associated with improved overall survival (OS) at P Results 119 patients were analyzed with a median follow-up of 2.78 years. Median age at diagnosis was 46 years, 56 (47%) were ER+/HER2-, 19 (16%) ER+/HER2+, 13 (11%) ER- /HER2+, and 31 (26%) ER-/HER2-, 86 (74%) had high grade histology, and 68 (57%) had cT3/T4 disease. Mastectomy was performed in 96 (81%) of patients, 36 (30%) had biopsy confirmed IMC involvement, and 8 (7%) had dissection of IM nodes. The median initial radiation dose was 50 Gy (range, 50-55), IMC boost 10 Gy (range, 8-16), and 41 (34%) received cumulative IMC dose > 60 Gy. The 3-year OS, FFDM, RC, and LC were 80%, 71%, 93%, and 94%, respectively. Patients with a nodal pCR of dissected nodes, had improved 3-year OS, 95% vs 71% (P = 0.008). Among patients who had a nodal pCR, nodal boost to > 60 Gy did not significantly improve 3-year OS, 100% vs. 93% (P = 0.40). In patients with less than a nodal pCR, who received IMC > 60 Gy, 3-year OS was numerically improved but was not statistically significant 81% vs. 64% (P = 0.33). In MVA, cumulative IMC dose > 60 Gy, nodal pCR, ER positivity, HER2 positivity, and lower clinical T-stage were independently associated with improved OS (Table 1). Conclusion Nodal pathologic response to NAC and cumulative IMC dose > 60 Gy were independently predictive for improved OS in patients with non-metastatic cN3b breast cancer treated with curative intent. Regional nodal control using a boost was excellent even among those with less than nodal pCR.