Racial disparities in treatment and outcomes between non-Hispanic Black and non-Hispanic White women with nonmetastatic inflammatory breast cancer.

PURPOSE: The incidence rate of inflammatory breast cancer (IBC) is higher among non-Hispanic Black (NHB) than non-Hispanic White (NHW) women. We examined the differences in treatment and outcomes between NHB and NHW women with IBC, accounting for demographic, clinicopathological, and socioeconomic factors. METHODS: We collected data from the Surveillance, Epidemiology, and End Results database for NHB and NHW women with IBC diagnosed between 2010-2016. We analyzed the odds of receiving chemotherapy, radiation, and surgery between NHB and NHW women. We evaluated overall survival (OS) with Kaplan-Meier methods and Cox proportional hazards methods. Competing risk analysis was used to compare the risk of breast cancer death between NHB and NHW women. We also evaluated the magnitude of survival disparities within the strata of demographic, socioeconomic, and treatment factors. RESULTS: Among 1,652 NHW and 371 NHB women with IBC, the odds of receiving chemotherapy, surgery, and radiation were similar for NHB and NHW. After 39-month follow-up, the median OS was 40 and 81 months for NHB and NHW, respectively (p < 0.0001). The risk of breast cancer death was higher for NHB than NHW women (5-year risk of breast cancer death, 51% vs. 35%, p < 0.0001). CONCLUSION: After adjustment for demographic, clinicopathological, and socioeconomic factors; NHB women with IBC had similar odds of receiving surgery, chemotherapy, and radiation therapy, but were more likely to die of the disease compared to their NHW counterparts. Our findings suggest the presence of masked tumor biology, treatment, or socioeconomic factors associated with race that can lead to worse IBC outcomes.

Inflammatory breast cancer, trimodal treatment, and mortality: Does where you live matter?

BACKGROUND: The objective of this study is to examine the associations among neighborhood socioeconomic status, trimodal treatment, and disease-specific mortality among inflammatory breast cancer patients using data from the Surveillance, Epidemiology, and End Results program. METHODS: Patients diagnosed with inflammatory breast cancer (T4d) from 2010 to 2016 were identified in the Surveillance, Epidemiology, and End Results program. The cohort was stratified into neighborhood socioeconomic status groups (low, middle, high) based on National Cancer Institute census tract-level index. Trimodal treatment was defined as receipt of modified radical mastectomy, chemotherapy, and radiation therapy. Bivariable analysis, log-rank test, and a Cox proportional hazards model (hazard ratio, 95% confidence interval) were conducted to evaluate the relationship between neighborhood socioeconomic status, trimodal treatment, and disease-specific mortality. RESULTS: In total, 4,374 patients met study criteria. There was no difference between the neighborhood socioeconomic status groups in receipt of trimodal treatment (P = .19). On multivariable analysis, there was no association between low neighborhood socioeconomic status (hazard ratio 1.13, 0.98-1.30; ref high neighborhood socioeconomic status) or middle neighborhood socioeconomic status (hazard ratio 1.01, 0.88-1.64; ref high neighborhood socioeconomic status) and disease-specific mortality. Notably, triple negative subtype (hazard ratio 2.66, 2.21-3.20; ref luminal A) and Black race (hazard ratio 1.41, 1.16-1.72; ref White) were associated with a higher disease-specific mortality. CONCLUSION: For inflammatory breast cancer patients in the Surveillance, Epidemiology, and End Results program, disease-specific mortality appears to be driven by tumor biology and patient characteristics instead of treatment disparities or neighborhood socioeconomic status.

Circulating PIK3CA mutation detection at diagnosis in non-metastatic inflammatory breast cancer patients.

Inflammatory breast cancer (IBC) is an aggressive BC subtype with poor outcomes. A targetable somatic PIK3CA mutation is reported in 30% of IBC, allowing for treatment by PI3Kα-specific inhibitors, such as alpelisib. The aim of this study was to evaluate the detection rate of circulating PIK3CA mutation in locally-advanced IBC (LAIBC) patients harbouring a PIK3CA mutation on initial biopsy. This monocentric retrospective study was based on available stored plasma samples and tumour biopsies at diagnosis from all LAIBC patients treated with neo-adjuvant chemotherapy (NCT) between 2008 and 2018 at the Centre Henri Becquerel. PIK3CA mutations (E542K, E545K, H1047R/L) were assessed by droplet digital PCR (ddPCR) in plasma samples and tumoral tissue at diagnosis. A total of 55 patients were included. Overall, 14/55 patients (25%) had a PIK3CA mutation identified on baseline biopsy (H1047R = 8; H1047L = 3; E545K = 2; E542K = 1). Among them, 11 (79%) patients had enough DNA for circulating DNA analyses, and corresponding circulating PIK3CA mutations were found in 6/11 (55%). Among the 41 patients without PIK3CA mutations on biopsy, 32 (78%) had enough DNA for circulating DNA analysis, and no circulating PIK3CA mutation was identified. Our results revealed no prognostic or predictive value of PIK3CA mutations at the diagnosis of non-metastatic IBC but highlighted the prognostic value of the cfDNA rate at diagnosis. Our study showed that a corresponding circulating PIK3CA mutation was identified in 55% of LAIBC patients with PIK3CA-mutated tumours, while no circulating mutation was found among patients with PI3KCA wild-type tumours.

Inflammatory breast cancer appearance at presentation is associated with overall survival.

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 < 0.0001). The multivariate Cox regression model adjusting for clinical staging (p < 0.0001) and TNBC status (<0.0001) demonstrated classic presentation score significantly associated with poorer OS time (HR 2.6, 95% CI 1.7-3.9, p < 0.0001). CONCLUSIONS: A triad of classic IBC signs independently predicted OS in patients diagnosed with IBC. Further work is warranted to understand the biology related to clinical signs and further extend the understanding of physical examination findings in IBC.

Dermal Lymphatic Invasion, Survival, and Time to Recurrence or Progression in Inflammatory Breast Cancer.

OBJECTIVES: Dermal lymphatic invasion (DLI) with tumor emboli is a common pathologic characteristic of inflammatory breast cancer (IBC), although its presence is not required for diagnosis. We examined whether documented DLI on skin biopsy was associated with survival and time to recurrence or progression in IBC. MATERIALS AND METHODS: A total of 340 women enrolled in the IBC Registry at Dana-Farber Cancer Institute between 1997 and 2019 were included in this study. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for associations of DLI and overall survival, time to locoregional recurrence/progression, and distant metastasis by stage at presentation. RESULTS: DLI was detected in 215 (63.2%) of IBC cases overall. At disease presentation, IBC with DLI had a higher prevalence of de novo metastases (37.7% vs. 26.4%), breast skin ulceration (6.1% vs. 2.4%), and lymphovascular invasion within the breast parenchyma (52.9% vs. 25.5%) and a lower prevalence of palpable breast mass (48.2% vs. 70.6%) than IBC without DLI. Over a median follow-up of 2.0 years, 147 deaths occurred. DLI was not associated with survival or recurrence in multivariable models (all P ≥0.10). For example, among women with stage III disease, hazard ratios (95% confidence intervals) for DLI presence was 1.29 (0.77-2.15) for overall survival, 1.29 (0.56-3.00) for locoregional recurrence, and 1.71 (0.97-3.02) for distant metastasis. CONCLUSION: Although the extent of tumor emboli in dermal lymphatics may be associated with biological features of IBC, DLI was not an independent prognostic marker of clinical outcomes in this study.

Nomograms for Estimating Cause-Specific Death Rates of Patients With Inflammatory Breast Cancer: A Competing-Risks Analysis.

PURPOSE: Inflammatory breast cancer (IBC) is a rare, aggressive and special subtype of primary breast cancer. We aimed to establish competing-risks nomograms to predict the IBC-specific death (BCSD) and other-cause-specific death (OCSD) of IBC patients. METHODS: We extracted data on primary IBC patients from the SEER (Surveillance, Epidemiology, and End Results) database by applying specific inclusion and exclusion criteria. Cumulative incidence function (CIF) was used to calculate the cumulative incidence rates and Gray's test was used to evaluate the difference between groups. Fine-Gray proportional subdistribution hazard method was applied to identify the independent predictors. We then established nomograms to predict the 1-, 3-, and 5-year cumulative incidence rates of BCSD and OCSD based on the results. The calibration curves and concordance index (C-index) were adopted to validate the nomograms. RESULTS: We enrolled 1699 eligible IBC patients eventually. In general, the 1-, 3-, and 5-years cumulative incidence rates of BCSD were 15.3%, 41.0%, and 50.7%, respectively, while those of OCSD were 3.0%, 5.1%, and 7.4%. The following 9 variables were independent predictive factors for BCSD: race, lymph node ratio (LNR), AJCC M stage, histological grade, ER (estrogen receptor) status, PR (progesterone receptor) status, HER-2 (human epidermal growth factor-like receptor 2) status, surgery status, and radiotherapy status. Meanwhile, age, ER, PR and chemotherapy status could predict OCSD independently. These factors were integrated for the construction of the competing-risks nomograms. The results of calibration curves and C-indexes indicated the nomograms had good performance. CONCLUSIONS: Based on the SEER database, we established the first competing-risks nomograms to predict BCSD and OCSD of IBC patients. The good performance indicated that they could be incorporated in clinical practice to provide references for clinicians to make individualized treatment strategies.

Update on systemic treatment for newly diagnosed inflammatory breast cancer.

Background: Inflammatory breast cancer (IBC) is a rare and aggressive disease, accounting for 2-4% of new cases of breast cancer. Owing to its aggressive nature, IBC represent approximately 8-10% of breast cancer deaths. Management of IBC requires a multidisciplinary team for decision-making involving a composite of systemic treatment, surgery, and radiation, or "Trimodality Treatment." Because of the rarity of the disease, systemic therapy of IBC traditionally has been extrapolated from non-IBC clinical trials. Aim of Review: The purpose of this review is to provide an overview of the development of systemic treatment of IBC from the past to the present by focusing on IBC clinical trials, including chemotherapy and targeted therapies. Key Scientific Concepts of Review: We discuss their effects on pathologic complete response (pCR) and survival outcomes, the predictive markers, and the adverse events of these therapies. Further, we summarized the current standard treatment stratified by molecular subtypes based on clinical data. Finally, we discuss the future trend of systemic therapy, including immunotherapy and ongoing IBC clinical trials.

Comparison of survival in non-metastatic inflammatory and other T4 breast cancers: a SEER population-based analysis.

BACKGROUND: Previous studies have reported poor survival rates in inflammatory breast cancer (IBC) patients than non-inflammatory local advanced breast cancer (non-IBC) patients. However, until now, the survival rate of IBC and other T4 non-IBC (T4-non-IBC) patients remains unexplored. METHODS: Surveillance, Epidemiology, and End Results (SEER) database was searched to identify cases with confirmed non-metastatic IBC and T4-non-IBC who had received surgery, chemotherapy, and radiotherapy between 2010 and 2015. IBC was defined as per the American Joint Committee on Cancer (AJCC) 7th edition. Breast Cancer-Specific Survival (BCSS) was estimated by plotting the Kaplan-Meier curve and compared across groups by using the log-rank test. Cox model was constructed to determine the association between IBC and BCSS after adjusting for age, race, stage of disease, tumor grade and surgery type. RESULTS: Out of a total of 1986 patients, 37.1% had IBC and mean age was 56.6 ± 12.4. After a median follow-up time of 28 months, 3-year BCSS rate for IBC and T4-non-IBC patients was 81.4 and 81.9%, respectively (log-rank p = 0.398). The 3-year BCSS rate in HR-/HER2+ cohort was higher for IBC patients than T4-non-IBC patients (89.5% vs. 80.8%; log-rank p = 0.028), and in HR-/HER2- cohort it was significantly lower for IBC patients than T4-non-IBC patients (57.4% vs. 67.5%; log-rank p = 0.010). However, it was identical between IBC and T4-non-IBC patients in both HR+/HER2- (85.0% vs. 85.3%; log-rank p = 0.567) and HR+/HER2+ (93.6% vs. 91.0%, log-rank p = 0.510) cohorts. After adjusting for potential confounding variables, we observed that IBC is a significant independent predictor for survival of HR-/HER2+ cohort (hazards ratio [HR] = 0.442; 95% CI: 0.216-0.902; P = 0.025) and HR-/HER2- cohort (HR = 1.738; 95% CI: 1.192-2.534; P = 0.004). CONCLUSIONS: Patients with IBC and T4-non-IBC had a similar BCSS in the era of modern systemic treatment. In IBC patients, the HR-/HER2+ subtype is associated with a better outcome, and HR-/HER2- subtype is associated with poorer outcomes as compared to the T4-non-IBC patients.

Wnt (canonical and non canonical) pathways in breast carcinoma with extensive vascular invasion and inflammatory breast carcinoma.

BACKGROUND: Breast carcinoma with extensive peritumoral vascular invasion (ePVI-BC) is a cancer with massive vascular invasion (>10) detected in more than one slide. This neoplasm shows clinic-pathological affinity with inflammatory breast carcinoma (IBC). In this paper we evaluate their biological relationship through the study of surrogate markers (ß-catenin and NFAT5) of Canonical (cWnt) and non-canonical (nWnt) Wnt pathways activation. METHODS: By immunoistochemistry, we investigate ß-catenin and NFAT5 in 39 IBC, 74 ePVI-BC and 84 control cases (CG-BC). RESULTS: cWnt was activated in 100 % of ePVI-BC, in 64 % of IBC and 10 % of CG-BC. nWnt was activated in 20 % of ePVI-BC, 50 % of IBC and 1% of CG-BC. The prognosis of carcinomas with nWnt activated was poor similar to IBC. The statistical analysis evidences as both the pathways are synergistic in malignant progression and survival time. ß-catenin show an important association with prognostic factors and NFAT5 shows a relevant prognostic role on OS (p = 1.5*10-6) and DFS (P = 1,2*10-4). nWnt is associated with a worse prognosis independently of cWnt. cWnt is associated with adverse prognosis (DFS p = 0.0469; OS p = 0.004891) but its prognostic role is indifferent in carcinoma with nWnt activated. CONCLUSIONS: Canonical Wnt pathway is involved in malignant progression with dominant role for vascular invasion whereas non canonical Wnt pathway plays an important role on survival time including the capacity to identify carcinomas with IBC-like prognosis. Furthermore ePVI may represent a "prodromal form of IBC" as demonstrated by its clinicopathological and biological similarity with IBC.

A high neutrophil-lymphocyte ratio and platelet-lymphocyte ratio are associated with a worse outcome in inflammatory breast cancer.

INTRODUCTION: Inflammatory breast cancer (IBC) is an uncommon, but aggressive form of breast cancer that accounts for a disproportionally high fraction of breast cancer related mortality. The aim of this study was to explore the peripheral immune response and the prognostic value of blood-based biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), in a large IBC cohort. PATIENTS & METHODS: We retrospectively identified 127 IBC patients and collected lab results from in-hospital medical records. The differential count of leukocytes was determined at the moment of diagnosis, before any therapeutic intervention. A cohort of early stage (n = 108), locally advanced (n = 74) and metastatic breast cancer patients (n = 41) served as a control population. RESULTS: The NLR was significantly higher in IBC compared to an early stage breast cancer cohort, but no difference between IBC patients and locally advanced breast cancer patients was noted. In the metastatic setting, there was also no significant difference between IBC and nIBC. However, a high NLR (>4.0) remained a significant predictor of worse outcome in IBC patients (HR: 0.49; 95% CI: 0.24-1.00; P = .05) and a lower platelet-lymphocyte ratio (PLR) (≤210) correlated with a better disease-free survival (DFS) (HR: 0.51; 95% CI: 0.28-0.93; P = .03). CONCLUSION: Patients with a high NLR (>4.0) have a worse overall prognosis in IBC, while the PLR correlated with relapse free survival (RFS). Since NLR and PLR were not specifically associated with IBC disease, they can be seen as markers of more extensive disease.

Biological subtype, treatment response and outcomes in inflammatory breast cancer using data from the National Cancer Database.

BACKGROUND: Although inflammatory breast cancer (IBC) is postulated to be a distinct biological entity, practice guidelines and previous data suggest that treatment and outcomes are influenced by standard approximated biological subtype. The aim of this study was validation in a large recent National Cancer Database (NCDB) patient cohort. METHODS: Patients with non-metastatic IBC treated in 2010-2015 with neoadjuvant systemic therapy and surgery were identified from the NCDB. Approximated biological subtypes were categorized as oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-), ER-/HER2- and HER2+. Total pathological complete response (pCR) was defined as ypT0/ypTis, ypN0. χ2 tests were used to compare pCR rates, and Kaplan-Meier curves and Cox proportional hazards regression to analyse overall survival. RESULTS: Among 4068 patients with IBC (median age 56 years), the approximated biological subtype was ER+/HER2- in 1575 (38·7 per cent), HER2+ in 1323 (32·5 per cent) and ER-/HER2- in 1170 (28·8 per cent). A total of 3351 patients (84·0 per cent) were cN+ at presentation, with no differences across subtypes. Total pCR rates varied significantly by subtype: ER+/HER2- (6·2 per cent), HER2+ (38·8 per cent), ER-/HER2- (19·1 per cent) (P < 0·001), as did breast pCR rates (10·4, 44·5 and 25·2 per cent respectively) and nodal pCR rates (16·9, 56·9 and 33·1 per cent). The 5-year overall survival rate varied significantly across subtypes (ER+/HER2- 64·9 per cent, HER2+ 74·0 per cent, ER-/HER2- 44·0 per cent; P < 0·001) and by pCR within subtypes (all P < 0·001). In multivariable analysis, ER-/HER2- subtype (hazard ratio 2·89 versus HER2+ as reference; P < 0·001) and absence of total pCR (hazard ratio 3·23; P < 0·001) predicted worse survival. CONCLUSION: Both treatment response and survival in patients with IBC varied with approximated biological subtype, as among other invasive breast cancers. These data support continued tailoring of systemic treatment to approximated biological subtype and highlight the recent improved outcomes in patients with HER2+ disease.

ANTECEDENTES: En tanto que el cáncer inflamatorio de mama (inflammatory breast cancer, IBC) se ha postulado como una entidad biológica distinta, las guías de práctica clínica y datos previos sugieren que el tratamiento y los resultados están influenciados por aproximación al subtipo biológico estándar. El objetivo de este estudio fue la validación en una cohorte reciente de pacientes incluidas en una extensa Base de Datos Nacional de Cáncer (National Cancer Database, NCDB). MÉTODOS: A partir de la NCDB, se identificaron las pacientes con IBC no metastásico tratadas en con neoadyuvancia sistémica y cirugía durante el periodo 2010-2015. El subtipo biológico aproximado se categorizó como ER+/HER2-, ER-/HER2- y HER2+. La respuesta patológica completa total (pathologic complete response, pCR) se definió como ypT0/ypTis, ypN0. Se utilizaron pruebas de ji al cuadrado para comparar las tasas de pCR y las curvas de Kaplan-Meier y la regresión de riesgos proporcionales de Cox para analizar la supervivencia global (overall survival, OS). RESULTADOS: En las 4.068 pacientes con IBC (mediana de edad 56 años), el subtipo biológico aproximado fue ER+/HER2- en 1.575 (39%), HER2+ en 1.323 (33%) y ER-/HER2- en 1.170 (29%). Un total de 3.351 pacientes (84%) eran cN+ en el momento de la presentación, sin diferencias entre los subtipos. Las tasas totales de pCR variaron significativamente en función del subtipo: ER+/HER2- (6%), HER2+ (39%), ER-/HER2- (19%), P < 0,001, así como las tasas de pCR de la mama (10%, 45%, 25%) y las tasas de pCR de los ganglios linfáticos (17%, 57%, 33%). La OS a los 5 años varió significativamente según los subtipos (ER+/HER2- 65%, HER2+ 74%, ER-/HER2- 44%, P < 0,001) y según la pCR en cada uno de los subtipo (en cada uno P < 0,01). En el análisis multivariable, el subtipo ER-/HER2- (cociente de riesgos instantáneos, hazard ratio, HR 2,9, P < 0,001 versus HER2+) y la ausencia de pCR total (HR 3,2, P < 0,001) predijeron una peor supervivencia. CONCLUSIÓN: Tanto la respuesta al tratamiento del IBC y como la supervivencia variaron en función del subtipo biológico aproximado, tal como sucede en otros cánceres de mama invasivos. Estos datos apoyan la importancia de continuar ajustando el tratamiento sistémico al subtipo biológico aproximado y resaltan la mejoría reciente de los resultados en las pacientes HER2+.

Breast tumor tissue inflammation but not lobular involution is associated with survival among breast cancer patients in the Multiethnic Cohort.

BACKGROUND: This study investigated the association of breast lobular involution status and three inflammatory markers as predictors of survival among breast cancer patients in the Multiethnic Cohort. METHODS: Lobular involution was evaluated in tissue sections of normal breast tissue and COX-2, TNF-α, and TGF-ß proteins were assessed by immunohistochemistry in tumor microarrays. A summary score added the expression levels of the three markers. Cox regression was applied to estimate hazard ratios (HRs) and 95 % confidence intervals (CI) with age as the time metric and adjustment for factors known to affect mortality. RESULTS: Among 254 women (mean age = 61.7 ± 8.7 years) with pathologic blocks and follow-up information, 54 all-cause and 10 breast cancer-specific deaths were identified after a mean follow-up time of 16.0 ± 3.1 years. For 214 participants, an inflammatory score was available and 157 women had information on lobular involution. Lobular involution was not significantly associated with survival. Expression of both COX-2 and TNF-α were significant predictors of lower survival (p = 0.02 and 0.04), while the association for TGF-ß was weaker (p = 0.09). When combined into one overall inflammation score, both intermediate (HR = 2.72; 95 % CI 0.90-8.28) and high (HR = 4.21; 95 % CI 1.51-11.8) scores were associated with higher mortality but only the latter was statistically significant. No significant association with breast cancer-specific mortality was detected. CONCLUSIONS: These results suggest that strong expression of inflammatory markers in breast tissue predicts a poorer prognosis possibly due to a system-wide state of chronic inflammation.

Extent of axillary surgery in inflammatory breast cancer: a survival analysis of 3500 patients.

PURPOSE: Inflammatory breast cancer (IBC) is an aggressive variant for which axillary lymph node (LN) dissection following neoadjuvant chemotherapy (NACT) remains standard of care. But with increasingly effective systemic therapy, it is unclear whether more limited axillary surgery may be appropriate in some IBC patients. We sought to examine whether extent of axillary LN surgery was associated with overall survival (OS) for IBC. METHODS: Female breast cancer patients with non-metastatic IBC (cT4d) diagnosed 2010-2014 were identified in the National Cancer Data Base. Cox proportional hazards modeling was used to estimate the association between extent of axillary surgery (≤ 9 vs ≥ 10 LNs removed) and OS after adjusting for covariates, including post-NACT nodal status (ypN0 vs ypN1-3) and radiotherapy receipt (yes/no). RESULTS: 3471 patients were included: 597 (17.2%) had cN0 disease, 1833 (52.8%) had cN1 disease, and 1041 (30%) had cN2-3 disease. 49.9% of cN0 patients were confirmed to be ypN0 on post-NACT surgical pathology. Being ypN0 (vs ypN1-3) was associated with improved adjusted OS for all patients. Radiotherapy was associated with improved adjusted OS for cN1 and cN2-3 patients but not for cN0 patients. Regardless of ypN status, there was a trend towards improved adjusted OS with having ≥ 10 (vs ≤ 9) LNs removed for cN2-3 patients (HR 0.78, 95% CI 0.60-1.01, p = 0.06) but not for cN0 patients (p = 0.83). CONCLUSIONS: A majority of IBC patients in our study presented with node-positive disease, and for those presenting with cN2-3 disease, more extensive axillary surgery is potentially associated with improved survival. For cN0 patients, however, more extensive axillary surgery was not associated with a survival benefit, suggesting an opportunity for more personalized care.

NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non-inflammatory breast cancers.

Inflammatory breast cancer (IBC) is the most pro-metastatic form of breast cancer. Better understanding of its pathophysiology and identification of actionable genetic alterations (AGAs) are crucial to improve systemic treatment. We aimed to define the DNA profiles of IBC vs noninflammatory breast cancer (non-IBC) clinical samples in terms of copy number alterations (CNAs), mutations, and AGAs. We applied targeted next-generation sequencing (tNGS) and array-comparative genomic hybridization (aCGH) to 57 IBC and 50 non-IBC samples and pooled these data with four public datasets profiled using NGS and aCGH, leading to a total of 101 IBC and 2351 non-IBC untreated primary tumors. The respective percentages of each molecular subtype [hormone receptor-positive (HR+)/HER2-, HER2+, and triple-negative] were 68%, 15%, and 17% in non-IBC vs 25%, 35%, and 40% in IBC. The comparisons were adjusted for both the molecular subtypes and the American Joint Committee on Cancer (AJCC) stage. The 10 most frequently altered genes in IBCs were TP53 (63%), HER2/ERBB2 (30%), MYC (27%), PIK3CA (21%), BRCA2 (14%), CCND1 (13%), GATA3 (13%), NOTCH1 (12%), FGFR1 (11%), and ARID1A (10%). The tumor mutational burden was higher in IBC than in non-IBC. We identified 96 genes with an alteration frequency (p < 5% and q < 20%) different between IBC and non-IBC, independently from the molecular subtypes and AJCC stage; 95 were more frequently altered in IBC, including TP53, genes involved in the DNA repair (BRCA2) and NOTCH pathways, and one (PIK3CA) was more frequently altered in non-IBC. Ninety-seven percent of IBCs displayed at least one AGA. This percentage was higher than in non-IBC (87%), notably for drugs targeting DNA repair, NOTCH signaling, and CDK4/6, whose pathways were more frequently altered (DNA repair) or activated (NOTCH and CDK4/6) in IBC than in non-IBC. The genomic landscape of IBC is different from that of non-IBC. Enriched AGAs in IBC may explain its aggressiveness and provide clinically relevant targets.

Aggressive Subsets of Metastatic Triple Negative Breast Cancer.

BACKGROUND: Relative to other metastatic breast cancer subtypes, metastatic triple-negative breast cancer (mTNBC) has a shorter duration of response to therapy and worse overall survival. Among patients with mTNBC, it is hypothesized that inflammatory breast cancer (IBC) and young women have particularly aggressive phenotypes. We investigated clinical and cell-free DNA (cfDNA) characteristics of inflammatory-mTNBC and young-mTNBC. PATIENTS AND METHODS: We evaluated 158 patients with mTNBC who were stratified into 3 groups: (1) IBC; (2) patients aged 45 years or younger at primary diagnosis without IBC (non-IBC young); and (3) patients over age 45 at diagnosis without IBC. We evaluated clinicopathologic characteristics, sites of metastasis, survival outcomes, and the fraction of DNA in circulation derived from tumor (TFx). RESULTS: Analysis of metastatic sites revealed that young patients without IBC had the most frequent lung metastases (P = .002). cfDNA analyses of first sample showed that TFx was highest in the non-IBC young group but not elevated in the IBC group (analysis of variance P = .056 for first TFx). Individually, median overall survival from metastatic diagnosis for the IBC group was 15.2 months; for the non-IBC young group, 21.2 months, and for the non-IBC over 45 group, 31.2 months. Patients with IBC and young patients without IBC had worse prognosis relative to patients over 45 without IBC (log-rank P = .023). CONCLUSIONS: Among patients with mTNBC in this single-institution cohort, patients with IBC and young patients without IBC had significantly worse overall survival compared with patients over 45 without IBC. Young patients without IBC had significantly higher cfDNA TFx, whereas patients with IBC did not have elevated TFx despite a poor prognosis. These findings demonstrate that further analyses of mTNBC subsets are warranted.

Construction and Validation of Nomograms for Predicting Overall Survival and Cancer-Specific Survival in Nonmetastatic Inflammatory Breast Cancer Patients Receiving Tri-Modality Therapy: A Population-Based Study.

BACKGROUND As the most aggressive breast cancer, inflammatory breast cancer (IBC) has a poor prognosis. However, analyzing the prognostic factors of IBC is challenging due to its rarity. We identified the prognostic factors to establish predictive tools for survival in nonmetastatic IBC patients who received tri-modality therapy. MATERIAL AND METHODS The data of 893 nonmetastatic IBC patients were acquired from the Surveillance, Epidemiology, and End Results (SEER) database. IBC was identified by "ICD-O-3=8530" or "AJCC T, 7th=T4d"). Patients were randomized to the training (n=668) and validation (n=225) cohorts. Prognostic factors were identified in the training cohort. Factors in the nomogram for overall survival (OS) were filtered by the least absolute shrinkage selection operator (LASSO) regression model. Factors selected by the competing-risk models were integrated to construct nomograms for breast cancer-specific survival (BCSS). Nomogram validation was performed in both cohorts. RESULTS The number of positive lymph nodes contributed the most to both nomograms. In the validation cohort, the C-indexes for OS and BCSS were 0.724 and 0.727, respectively. Calibration curves demonstrated acceptable agreement between predicted and actual survival. Risk scores were calculated from the nomograms and used to split patients into the low-risk and high-risk groups. Smooth hazard ratio (HR) curves and Kaplan-Meier curves showed a statistically significant difference in prognosis between the high-risk group and low-risk group (log-rank P<0.001). CONCLUSIONS We unveiled the prognostic factors of nonmetastatic IBC and formulated nomograms to predict survival. In these models, the likelihood of individual survival can be easily calculated, which may assist clinicians in selecting treatment regimens.

Construction and validation of a nomogram to predict overall survival in patients with inflammatory breast cancer.

In the present study, we examined the factors affecting survival of women with inflammatory breast cancer (IBC) and constructed and validated a nomogram to predict overall survival (OS) in these patients. The cohort was selected from the Surveillance, Epidemiology, and End Results (SEER) program between 1 January 2004 and 31 December 2013. Univariate and multivariate Cox proportional hazards regression models were constructed. A nomogram was developed based on significant prognostic indicators of OS. The discriminatory and predictive capacities of the nomogram were assessed using Harrell's concordance index (C-index) and calibration plots. A total of 1651 eligible patients were identified, with a median survival time of 31 months (range 0-131 months), and the 3- and 5-year OS rates were 52.8% and 39.5%, respectively. Multivariate analysis revealed that race (P < .001), marital status (P = .011), N stage (P = .002), M stage (P < .001), hormone receptor (P < .001), human epidermal growth factor receptor-2 (HER2) (P = .001), surgery (P < .001), chemotherapy (P < .001), and radiotherapy (P = .010) were independent prognostic indicators of IBC. These nine variables were incorporated to construct a nomogram. The C-indexes of the nomogram were 0.738 (95% confidence interval [CI]: 0.717, 0.759) and 0.741 (95% CI: 0.717, 0.765) for the internal and external validations, respectively. The nomogram had a better discriminatory capacity for predicting OS than did the SEER summary stage (P < .001) or the American Joint Committee on Cancer tumor-node metastasis staging systems (8th edition; P < .001). The calibration plot revealed satisfactory agreement between the findings and predicted outcomes in both the internal and external validations. The nomogram-based 3- and 5-year OS predictions for patients with IBC exhibited superior accuracy over the existing models.

Marital status is an independent prognostic factor in inflammatory breast cancer patients: an analysis of the surveillance, epidemiology, and end results database.

OBJECTIVES: The aim of this analysis was to study the impact of marital status on inflammatory breast cancer (IBC) patients, as the prognostic impact is yet to be studied in detail. METHODS: Data of IBC patients from 2004 to 2010 were sorted out from the database of surveillance, epidemiology, and end results (SEER), and overall survival (OS) rates and breast cancer-specific survival (CSS) rates were compared between a group of married and unmarried patients. The comparison was performed by Kaplan-Meier method with log-rank test, and multivariate survival analysis of CSS and OS was performed using the Cox proportional hazard model. RESULTS: Data of 1342 patients were collected from the SEER database, on an average 52% of married patients (n = 698, 52.01%) and 48% of unmarried patients (n = 644, 47.99%) for this analysis. Married patients were more likely to be more younger (aged ≤ 56) (52.44% vs. 43.94%), white ethnicity (83.24% vs. 71.58%), HoR positive (48.28% vs. 41.61%), more patients received surgery (78.51% vs. 64.60%), chemotherapy (90.69% vs. 80.12%) and radiotherapy (53.44% vs. 44.41%) compared to unmarried group, and less likely to be AJCC stage IV (26.22% vs. 35.40%) (All P ˂ 0.05). Married patients had better 5-year CSS (74.90% vs. 65.55%, P < 0.0001) and OS rates (45.43% vs. 33.11%, P < 0.0001). The multivariate analysis revealed that marital status is an independent prognostic factor, whereas the data of unmarried patients showed worse CSS (HR 1.188; 95% CI 1.033-1.367; P = 0.016) and OS rates (HR 1.245; 95% CI 1.090-1.421; P = 0.001).The subgroup analysis further revealed that the OS and CSS rates in the married group were better than the unmarried group, regardless of different AJCC stages. CONCLUSION: Marital status was an independent prognostic indicator in IBC patients. As the study reveals, the CSS and OS rates of the married patients were better than those of the unmarried patients.

Nomogram for predicting the overall survival of patients with inflammatory breast cancer: A SEER-based study.

OBJECTIVES: Inflammatory breast cancer (IBC) is a rare malignancy that is a unique biologic subtype of breast cancer. A nomogram to predict the overall survival (OS) of IBC patients is lacking. The aim of the study was to construct and validate a nomogram to predict the OS of IBC patients based on the Surveillance, Epidemiology, and End Results (SEER) Program. METHODS: Patients diagnosed with IBC between 2010 and 2016 were selected from the SEER database. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors. A nomogram was constructed to predict the 1-, 3- and 5-year OS of these patients. The nomogram was internally and externally validated by Harrell's C-indexes and calibration plots. RESULTS: Patients were randomly divided into a training set (n = 2464) and a validation set (n = 1052). The training set was used to establish a nomogram. Multivariate analysis identified that race, age at diagnosis, breast cancer subtype, grade, N stage, M stage, radiation, chemotherapy, and surgery were significant prognostic factors for the OS. The internally and externally validated Harrell's C-indexes were 0.763 and 0.786, respectively. The calibration plots for predictions of the 1-, 3-, and 5-year OS were in excellent agreement. CONCLUSIONS: A nomogram was constructed to predict the OS for IBC patients based on the SEER database and to provide accurate and individualised survival predictions.

Poor Response to Neoadjuvant Chemotherapy Correlates with Mast Cell Infiltration in Inflammatory Breast Cancer.

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.