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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.

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Our understanding is limited concerning the tumor immune microenvironment of inflammatory breast cancer (IBC), an aggressive form of primary cancer with low rates of pathologic complete response to current neoadjuvant chemotherapy (NAC) regimens. We retrospectively identified pretreatment (N = 86) and matched posttreatment tissue (N = 27) from patients with stage III or de novo stage IV IBC who received NAC followed by a mastectomy. Immune profiling was performed including quantification of lymphoid and myeloid infiltrates by IHC and T-cell repertoire analysis. Thirty-four of 86 cases in this cohort (39.5%) achieved a pathologic complete response. Characterization of the tumor microenvironment revealed that having a lower pretreatment mast cell density was significantly associated with achieving a pathologic complete response to NAC (P = 0.004), with responders also having more stromal tumor-infiltrating lymphocytes (P = 0.035), CD8+ T cells (P = 0.047), and CD20+ B cells (P = 0.054). Spatial analysis showed close proximity of mast cells to CD8+ T cells, CD163+ monocytes/macrophages, and tumor cells when pathologic complete response was not achieved. PD-L1 positivity on tumor cells was found in fewer than 2% of cases and on immune cells in 27% of cases, but with no correlation to response. Our results highlight the strong association of mast cell infiltration with poor response to NAC, suggesting a mechanism of treatment resistance and a potential therapeutic target in IBC. Proximity of mast cells to immune and tumor cells may suggest immunosuppressive or tumor-promoting interactions of these mast cells.

Supplementary Data File and Legend PDF file - 113K, Supplementary Data File and legend

Supplementary Tables XLS file - 236K, Supplementary Table 1: Comparison of ER- and ErbB2-status determined using gene expression profiling and immunohistochemistry Supplementary Table 2: Validation of the algorithm to identify transcription factor activation Supplementary Table 3: Description of the public nIBC data sets Supplementary Table 4: Molecular data of IBC and nIBC samples Supplementary Table 5: List of 491 probe sets differentially expressed between IBC and nIBC samples in a molecular subtype-independent manner Supplementary Table 6: IPA analysis of the list of 443 unique genes differentially expressed between IBC and nIBC Supplementary Table 7: Networks identified by IPA analysis of the list of 443 unique genes differentially expressed between IBC and nIBC Supplementary Table 8: Uni- and multivariate analyses for DMFS in the public pooled nIBC data set

Background: Inflammatory breast cancer (IBC) is a poorly characterized form of breast cancer. So far, the results of expression profiling in IBC are inconclusive due to various reasons including limited sample size. Here, we present the integration of three Affymetrix expression datasets collected through the World IBC Consortium allowing us to interrogate the molecular profile of IBC using the largest series of IBC samples ever reported.Experimental Design: Affymetrix profiles (HGU133-series) from 137 patients with IBC and 252 patients with non-IBC (nIBC) were analyzed using unsupervised and supervised techniques. Samples were classified according to the molecular subtypes using the PAM50-algorithm. Regression models were used to delineate IBC-specific and molecular subtype-independent changes in gene expression, pathway, and transcription factor activation.Results: Four robust IBC-sample clusters were identified, associated with the different molecular subtypes (P < 0.001), all of which were identified in IBC with a similar prevalence as in nIBC, except for the luminal A subtype (19% vs. 42%; P < 0.001) and the HER2-enriched subtype (22% vs. 9%; P < 0.001). Supervised analysis identified and validated an IBC-specific, molecular subtype-independent 79-gene signature, which held independent prognostic value in a series of 871 nIBCs. Functional analysis revealed attenuated TGF-β signaling in IBC.Conclusion: We show that IBC is transcriptionally heterogeneous and that all molecular subtypes described in nIBC are detectable in IBC, albeit with a different frequency. The molecular profile of IBC, bearing molecular traits of aggressive breast tumor biology, shows attenuation of TGF-β signaling, potentially explaining the metastatic potential of IBC tumor cells in an unexpected manner. Clin Cancer Res; 19(17); 4685–96. ©2013 AACR.

Supplementary Figures PDF file - 529K, Supplementary Figure 1: Application of the Gaussian mixture model to ESR1- and ERBB2-expression data Supplementary Figure 2: Normalization Supplementary Figure 3: Silhouette Analysis Supplementary Figure 4: Silhouette Analysis (P-Values) Supplementary Figure 5: Validation of Limma-corrected IBC/nIBC signature Supplementary Figure 6: Networks overrepresented in IBC Supplementary Figure 7: Networks overrepresented in nIBC Supplementary Figure 8: Prognostic value of the IBC/nIBC signature in nIBC

PDF file, 351K, Silencing endogenous TIG1 in SUM149 IBC cells inhibits cell proliferation (S1); Silencing endogenous TIG1 in KPL-4 IBC cells inhibits cell proliferation, migration, and invasion (S2); TIG1 depletion affects the growth of SUM149 cells in 3-dimensional culture (S3); Heat map of 19 selected candidates from 183 probe sets differentially expressed between SUM149 cells transfected with control siRNA and SUM149 cells transfected with siRNA targeting TIG1 (siTIG1)(S4); Representative images of crystal violet staining of migration and invasion assays for Axl-restored shTIG1-A cells (S5); TIG1 colocalized with Axl in KPL-4 cells (S6); SGI-7079 treatment inhibits the invasion of KPL-4 cells (S7).

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PDF file, 72K, Candidate functional partners of TIG1 selected using DNA microarray analysis.

PDF file, 76K, Relation between TIG1 expression status and clinicopathologic factors of the IBC patient tissues.

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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.

Summary Background Matricellular proteins comprising matrisome and adhesome are responsible for structure integrity and interactions between cells in the tumour microenvironment of breast cancer. Changes in the gene expression of matrisome and adhesome augment metastasis. Since inflammatory breast cancer (IBC) is characterized by high metastatic behaviour. Herein, we compared the gene expression profile of matrisome and adhesome in non-IBC and IBC in fresh tissue and ex vivo patient-derived explants (PDEs) and we also compared the secretory inflammatory mediators of PDEs in non-IBC and IBC to identify secretory cytokines participate in cross-talk between cells via interactions with matrisome and adhisome. Methods Fifty patients (31 non-IBC and 19 IBC) were enrolled in the present study. To test their validation in clinical studies, PDEs were cultured as an ex vivo model. Gene expression and cytokine array were used to identify candidate genes and cytokines contributing to metastasis in the examined fresh tissues and PDEs. Bioinformatics analysis was applied on identified differentially expressed genes using GeneMANIA and Metascape gene annotation and analysis resource to identify pathways involved in IBC metastasis. Results Normal and cancer fresh tissues and PDEs of IBC were characterized by overexpression of CDH1 and MMP14 and downregulation of CTNNA1 and TIMP1 compared with non-IBC. The secretome of IBC cancer PDEs is characterized by significantly high expression of interleukin 6 and monocyte chemoattractant protein-1 (CCL2) compared with non-IBC. Conclusion Genes expressed by adhisome and matrisome play a significant role in IBC metastasis and should be considered novel target therapy.

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.

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.

Inflammatory breast cancer (IBC) is a rare and aggressive subtype of breast cancer characterized by rapid progression and early metastasis, often with advanced nodal locations, including the supraclavicular (SCV) nodal basin. Previously considered M1 disease, ipsilateral clinical supraclavicular node involvement (N3c) disease is now considered locally advanced disease and warrants treatment with intent to cure. The objective of this study was to evaluate the long-term outcomes of patients with IBC and N3c disease.This study was conducted using a prospectively collected database of all patients with IBC treated at a dedicated cancer center from 2007 to 2019. Surgical patients with SCV nodal involvement and complete follow-up were identified. Our primary outcome was 5-year overall survival (OS). Multivariate Cox proportional hazards models were used to determine predictors for survival. Event-free survival (EFS) and OS were calculated using the Kaplan-Meier method.There were 70 patients who met inclusion criteria. All patients underwent comprehensive trimodality therapy. The majority of patients had complete (66.2%) radiologic response in the SCV nodal basins following neoadjuvant therapy. Six patients (8.6%) had a locoregional recurrence, with two (2.9%) occurring in the supraclavicular fossa. The 5-year OS was 60.2% [95% confidence interval (CI) 47.7-72.7%]. Increasing age (hazard ratio 2.7; p = 0.03) and triple-negative subtype (hazard ratio 4.9; p = 0.03) were associated with poor OS. The 5-year EFS was 56.1% (95% CI 40.9-68.8%). The presence of more than ten positive axillary nodes on final surgical pathology (hazard ratio 5.5; p = 0.01) predicted poor EFS.With comprehensive trimodality therapy and multidisciplinary team approach, patients with IBC with supraclavicular nodal involvement experience excellent locoregional control and favorable survival.

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.

The standard of care for inflammatory breast cancer (IBC) is neoadjuvant chemotherapy, total mastectomy with axillary lymph node dissection (ALND), and postmastectomy radiation therapy. Existing studies suggest that sentinel lymph node biopsy (SLNB) may not be reliable in IBC. The use and frequency of SLNB in women with IBC is not well characterized.To determine the frequency and temporal trend of SLNB in patients with IBC.This retrospective cohort study used the National Cancer Database, a nationwide hospital-based cancer registry, and included women who were diagnosed with nonmetastatic IBC and underwent axillary surgery from 2012 to 2017. Data were analyzed from January 2021 to May 2021.Any SLNB, including SLNB alone and SLNB followed by ALND, and ALND alone.Scatterplot fit with a linear regression model were used to evaluate the yearly increase of any SLNB use. Multivariable logistic regression models to evaluate the association of study variables with the outcome of any SLNB.This study included a total of 1096 women (mean [SD] age, 56.1 [12.9] years) who were 18 years or older with nonmetastatic IBC diagnosed between 2012 and 2017. Of the 186 of 1096 women (17%) who received any SLNB, 137 (73.7%) were White individuals; and of the 910 of 1096 women (83%) who received an ALND only, 676 (74.3%) were White individuals. Among women undergoing any SLNB, 119 of 186 (64%) did not undergo a completion ALND. There was a statistically significant increasing trend in the use of SLNB from 2012 to 2017 (22 of 205 patients [11%] vs 32 of 148 patients [22%]; P = .004). In multivariable analysis, the use of SLNB was associated with diagnosis year (2017 vs 2012; odds ratio [OR], 2.26; 95% CI, 1.26-4.20), clinical nodal status (cN3 vs 0; OR, 0.39; 95% CI, 0.22-0.67), and receipt of reconstructive surgery (OR, 1.80; 95% CI, 1.09-2.96).The findings of this cohort study suggest that there is frequent and increasing use of SLNB in patients with IBC that is not evidence-based or supported by current treatment guidelines.

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.

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.

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/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.

PURPOSE/OBJECTIVE(S) Twice daily accelerated partial breast irradiation (APBI) may confer worse long-term cosmetic outcome than daily whole breast irradiation (WBI). We hypothesized that daily partial breast irradiation would yield improved cosmetic outcomes without compromising tumor control. To test this hypothesis, we conducted a phase II trial to evaluate a ten-fraction regimen of daily PBI (OPAL regimen). MATERIALS/METHODS From 2017-2018, 149 women aged ≥ 50 with DCIS or early invasive, ER+ breast cancer were enrolled into a multi-institutional phase II trial that treated the partial breast to 35 Gy in 10 daily fractions. Patients with close margins (< 2 mm) also received a boost of 9 Gy in 3 daily fractions. Toxicities were evaluated using CTCAE v4.0 and physician-reported cosmesis was assessed using the RTOG scale. The Breast Cancer Treatment Outcomes Scale (BCTOS) assessed patient-reported cosmesis, breast pain, and functional status. Outcomes were assessed at baseline, 6 months, 1 year, and annually thereafter. The primary outcome was incidence of grade ≥ 2 toxicity within 6 months of PBI initiation. To facilitate a comparison of the OPAL regimen to WBI, we identified 176 patients with similar clinical-pathologic features from our prior trial of WBI+boost in which toxicities were also prospectively collected. Differences in cross-sectional outcomes between the OPAL trial and historical WBI+boost cohort were tested using chi-square test. Mixed effect growth curve models evaluated outcomes over time adjusting for relevant covariates. RESULTS Median age was 64 years and median follow-up was 2 years. All 149 patients received 35 Gy in 10 daily fractions and 26 received a boost. One patient developed an in-field DCIS recurrence. For the primary outcome, grade ≥ 2 toxicity within 6 months of PBI initiation was 14.1% with OPAL compared to 71% in the WBI+boost cohort (P < 0.001). At two years post-radiation, fatigue (8% vs 16%), hyperpigmentation (18% vs 30%), breast edema (0% vs 9%), superficial fibrosis (18% vs 31%), deep fibrosis (6% vs 13%), nipple areolar changes (6% vs 17%), and breast atrophy (19% vs 35%) were less prevalent in patients treated with OPAL (all P < 0.05). At two years, 93% of patients treated with OPAL had excellent/good cosmetic outcome compared to 77% of patients treated with WBI+boost (P < 0.001). In multivariable longitudinal analysis, treatment with OPAL was associated with improved patient-reported cosmetic outcome (P < 0.001), functional status (P = 0.02), breast pain (P = 0.003) and physician-reported cosmetic outcome (P < 0.001). CONCLUSION Treatment with this novel daily PBI regimen of 35 Gy in 10 daily fractions with selective boost yielded better cosmetic and functional outcomes and less breast pain and toxicity than WBI+boost with median follow up of 2 years. Daily external beam partial breast irradiation with 10 or fewer fractions merits further prospective evaluation.

Purpose/Objective(s) Surgery remains the foundation of curative therapy for non-metastatic breast cancer, but a substantial proportion of patients do not undergo surgery. Evidence is limited regarding overall survival (OS) outcomes and factors associated with lack of surgery. We sought to measure OS among patients with breast cancer who do not undergo surgery, and assess factors for association with lack of surgery and OS. Materials/Methods Retrospective cohort study of patients in the US National Cancer Data Base from 2004–2016. The dataset comprised 2,696,734 patients; excluding patients with unknown surgical status or stage IV, cT0, cTx, or pIS, metastatic or recurrent disease resulted in 1,192,294 patients for analysis. Descriptive statistics were used to summarize patient characteristics. Chi-square tests and Wilcoxon rank-sum were used to test for differences between variables between groups. OS was analyzed utilizing the Kaplan-Meier method for non-surgical patients diagnosed in 2010–2015 to account for receptor status (Median follow-up time 34 months). The Cox proportional hazards model was used to assess association of risk factors with OS. Results Of the 1,192,294 patients, 50,626 (4.3%) did not undergo surgery. Socioeconomic factors that were more prevalent in the non-surgical cohort were Black race, age > 50 years, lower income, uninsured or public insurance, and lower education; this group was also more likely to have more comorbidities, higher disease stage, and more aggressive disease biology. Only 3,689 non-surgical patients (7.3%) received radiation therapy (RT). Median OS time for all patients who did not have surgery was 58 months (3-year and 5-year OS rates 63% and 49%). Median OS times were longer for patients who received chemotherapy (80 vs 50 months) and RT (85 vs 56 months). On multivariate analysis, age, race, income, insurance status, comorbidity score, disease stage, tumor subtype treatment facility type and location, and receipt of RT were associated with OS. On subgroup analysis, receipt of chemotherapy improved OS for patients with high-risk (triple-negative, HER2+) disease, whereas receipt of RT led to improved OS for patients with ER+ and favorable (ER+, early-stage, age > 60) disease. Conclusion More than 4% of women with non-metastatic breast cancer do not undergo surgery for their cancer, particularly those with more aggressive disease, of minority race/ethnicity and lower socioeconomic status. Despite its known benefits, RT was significantly underused. This study provides one of the first benchmarks of survival outcomes for patients who do not undergo surgery for breast cancer, and highlights a potential role for increased use of RT. Additionally this report highlights significant disparities effecting women of minority race/ethnicity and lower socioeconomic status.

The purpose of this narrative review is to summarize the contributors to misdiagnosis or delayed diagnosis of inflammatory breast cancer (IBC) and strategies for expedient diagnosis.Patients with IBC often report the disease as initially being misdiagnosed, most commonly as mastitis.We reviewed the literature on this challenging diagnosis by using sequential PubMed search criteria including IBC breast symptoms, IBC diagnosis, and IBC imaging modalities to augment the authors' knowledge of IBC. Other references were added from the manuscripts identified in the PubMed searches and from manuscript reviewers.Several factors contribute to the delayed diagnosis of IBC. One important factor is that IBC is uncommon, and many generalists may not be aware of it in the differential diagnosis of breast skin symptoms. Several features of IBC contribute to the low sensitivity of mammography for its detection, and so the diagnosis is based on clinical factors and is thereby subjective. The presentation can be highly varied; classic textbook images that do not capture the range of presenting signs and symptoms across skin tones may contribute to missed diagnoses in patients with atypical presentations. In fact, the staging system of the American Joint Committee on Cancer, which requires erythema of the breast skin for diagnosis, may exclude patients with obvious global breast skin findings that are not explicitly red. We present an adapted algorithm for working up the undiagnosed inflammatory breast to ensure the timely and accurate diagnosis of IBC. We assert that frank, non-erythematous global skin signs in an enlarged breast with diffuse breast malignancy are sufficient to diagnose IBC if the timing of these signs and findings on biopsy are consistent. We further provide images of atypical IBC identified by global breast skin signs, including peau d'orange, consistent with IBC in the absence of frank erythema.

PURPOSE/OBJECTIVE(S) To report outcomes for women with pT1-2N1M0 breast cancer undergoing mastectomy and sentinel lymph node biopsy (SLNB) without completion axillary dissection, and to investigate the effect of post-mastectomy radiation therapy (PMRT). MATERIALS/METHODS Data from 5 North American institutions were pooled to include women with pT1-2N1M0 breast cancer from 1997-2015 who underwent mastectomy with a positive SLNB and ≤ 5 lymph nodes (LNs) resected. All patients were clinically N0 and none received neoadjuvant chemotherapy. Competing-risks regression was performed to identify factors associated with overall recurrence (OR), inclusive of locoregional (LR) and distant recurrence (DM). RESULTS Among 871 patients included, median age at diagnosis was 57 years, 92% were ER/PR-positive, 85% HER2-negative, and 60% received adjuvant chemotherapy. The 500 (57%) patients who received PMRT were significantly younger, had larger tumors, more positive LN, lymphovascular invasion (LVI), extracapsular extension (ECE), HER2-positive disease, and more frequently received adjuvant chemotherapy (all P < 0.05) compared to those not receiving PMRT. Median number of lymph nodes sampled in each group was 3 (range: 1-5). At a median follow up of 5.2 years, the 5-year cumulative incidence rates of LR, DM, OR, and breast cancer mortality (BCM) were 2%, 4%, 5%, and 3%, respectively. The 5-year rates of disease-free survival (DFS) and overall survival (OS) were 87% and 91%. LR was the only endpoint with a statistically significant difference between those receiving PMRT (0.4%) as compared to those without PMRT (3.9%), P < 0.001. On univariable competing risks regression, tumor size, nodal ratio, grade, LVI, and ER/PR status were significantly associated with OR and were included in multivariable analysis. On multivariable competing risks regression, larger tumor size (HR 1.47, 95% CI 1.19-1.81, P < 0.001), grade III (HR 1.81, 95% CI 1.07-3.05, P = 0.03), higher nodal ratio (HR 2.86, 95% CI 1.01-7.69, P = 0.049), and LVI (HR 2.04, 95% CI 1.27-3.28, P = 0.003) were significantly associated with increased risk of OR. PMRT was associated with decreased risk of OR (HR 0.60, 95% CI 0.26-1.00, P = 0.05), though this effect did not reach statistical significance. CONCLUSION In selected patients undergoing mastectomy and SLNB without completion axillary dissection for pT1-2N1 breast cancer, larger tumor size, higher grade, increased nodal ratio and the presence of LVI are associated with increased risk of overall recurrence. Further studies are needed to identify which subset of patients may benefit most from PMRT.

Purpose/Objective(s) Breast cancer patients with clinical N3c (cN3c) disease at diagnosis have poor outcomes relative to other breast cancer patients. Radiotherapy (RT) has an important role in the management of these patients as the supraclavicular (SCV) nodes are not routinely surgically dissected. However, outcomes and prognostic factors in the era of modern neoadjuvant chemotherapy (NAC) are not well-described. Materials/Methods We reviewed breast cancer patients with non-metastatic cN3c disease treated at our institution from 2014-2019 with curative intent NAC, surgery, and adjuvant RT. All patients received nodal RT including the SCV, infraclavicular, and internal mammary nodes. Institutional guidelines recommend a 10 Gy boost to clinically resolved N3 nodal basins and 16 Gy to unresolved N3 nodes. Variables including initial and boost dose, pathologic response, and type of nodal dissection were collected. Local (LC) and regional control (RC), freedom from distant metastases (FFDM), and overall survival (OS) were analyzed with the Kaplan Meier method. A saturated multivariable Cox proportional hazards model of OS with backward elimination identified clinical variables associated with OS at P Results A total of 176 consecutive patients were analyzed. The median follow-up time was 2.83 years. The median age was 54 years, 76 (43%) were ER+/HER2-, 20 (11%) ER+/HER2+, 26 (15%) ER-/HER2+, and 54 (31%) ER-/HER2-. 102 (57%) had T3/4 disease, 41 (23%) underwent lumpectomy, 142 (81%) had pathologic confirmation of N3c, and 10 (6%) had a neck dissection. The median initial radiation dose was 50 Gy (range, 44-56.25), SCV boost 10 Gy (range, 6-16), and 156 (89%) received cumulative SCV dose ≥60 Gy. The 3-year OS, FFDM, RC, and LC were 79%, 64%, 93%, and 96%, respectively. For cumulative SCV dose of ≥60 Gy vs. Conclusion In a large, modern cohort of non-metastatic cN3c breast cancer patients treated with multimodality therapy, cumulative SCV dose ≥60 Gy was found to be associated with improved OS. Although optimal radiation dosing cannot be established from this data, a SCV radiation boost should be considered in cN3c patients treated with curative intent respecting normal tissue constraints.