Hormone receptor and HER2 molecular subtypes had limited predictive and prognostic power in our IBC population. All molecular subtypes of IBC had a poor prognosis. HR-positive status did not necessarily confer a good prognosis. For all IBC subtypes, novel, specific treatment strategies are needed in the neoadjuvant and adjuvant settings.

Background:Some studies have suggested that statins, which have cholesterol-lowering and anti-inflammatory properties, may have antitumor effects. Effects of statins on inflammatory breast cancer (IBC) have never been studied.Methods:We reviewed 723 patients diagnosed with primary IBC in 1995–2011 and treated at The University of Texas MD Anderson Cancer Center. Statin users were defined as being on statins at the initial evaluation. Based on Ahern et al's statin classification (JNCI, 2011), clinical outcomes were compared by statin use and type (weakly lipophilic to hydrophilic (H-statin) vs lipophilic statins (L-statin)). We used the Kaplan–Meier method to estimate the median progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS), and a Cox proportional hazards regression model to test the statistical significance of potential prognostic factors.Results:In the multivariable Cox model, H-statins were associated with significantly improved PFS compared with no statin (hazard ratio=0.49; 95% confidence interval=0.28–0.84; P<0.01); OS and DSS P-values were 0.80 and 0.85, respectively. For L-statins vs no statin, P-values for PFS, DSS, and OS were 0.81, 0.4, and 0.74, respectively.Conclusion:H-statins were associated with significantly improved PFS. A prospective randomised study evaluating the survival benefits of statins in primary IBC is warranted.

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Reported rates of local failure after adjuvant radiation for women with inflammatory breast cancer (IBC) and triple-negative non-IBC are higher than those of women with receptor-expressing non-IBC. These high rates of locoregional recurrence are potentially influenced by the contribution of radioresistant cancer stem cells to these cancers. Statins have been shown to target stem cells and improve disease-free survival among IBC patients. We examined simvastatin radiosensitization of multiple subtypes of breast cancer cell lines in vitro in monolayer and mammosphere-based clonogenic assays and examined the therapeutic benefit of statin use on local control after postmastectomy radiation (PMRT) among IBC patients. We found that simvastatin radiosensitizes mammosphere-initiating cells (MICs) of IBC cell lines (MDA-IBC3, SUM149, SUM190) and of the metaplastic, non-IBC triple-negative receptor cell line (SUM159). However, simvastatin radioprotects MICs of non-IBC cell lines MCF-7 and SKBR3. In a retrospective clinical study of 519 IBC patients treated with PMRT, 53 patients used a statin. On univariate analysis, actuarial 3-year local recurrence-free survival (LRFS) was higher among statin users, and on multivariate analysis, triple negative breast cancer, absence of lymphatic invasion, neoadjuvant pathological tumor response to preoperative chemotherapy, and statin use were independently associated with higher LRFS. In conclusion, patients with IBC and triple-negative non-IBC breast cancer have the highest rates of local failure, and there are no available known radiosensitizers. We report significant improvement in local control after PMRT among statin users with IBC and significant radiosensitization across triple-negative and IBC cell lines of multiple subtypes using simvastatin. These data suggest that simvastatin should be justified as a radiosensitizing agent by a prospective clinical trial.

IntroductionBecause of its high rate of metastasis, inflammatory breast cancer (IBC) has a poor prognosis compared with non-inflammatory types of breast cancer (non-IBC). In a recent study, Lehmann and colleagues identified seven subtypes of triple-negative breast cancer (TNBC). We hypothesized that the distribution of TNBC subtypes differs between TN-IBC and TN-non-IBC. We determined the subtypes and compared clinical outcomes by subtype in TN-IBC and TN-non-IBC patients.MethodsWe determined TNBC subtypes in a TNBC cohort from the World IBC Consortium for which IBC status was known (39 cases of TN-IBC; 49 cases of TN-non-IBC). We then determined the associations between TNBC subtypes and IBC status and compared clinical outcomes between TNBC subtypes.ResultsWe found the seven subtypes exist in both TN-IBC and TN-non-IBC. We found no association between TNBC subtype and IBC status (P = 0.47). TNBC subtype did not predict recurrence-free survival. IBC status was not a significant predictor of recurrence-free or overall survival in the TNBC cohort.ConclusionsOur data show that, like TN-non-IBC, TN-IBC is a heterogeneous disease. Although clinical characteristics differ significantly between IBC and non-IBC, no unique IBC-specific TNBC subtypes were identified by mRNA gene-expression profiles of the tumor. Studies are needed to identify the subtle molecular or microenvironmental differences that contribute to the differing clinical behaviors between TN-IBC and TN-non-IBC.

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Purpose We previously demonstrated that cholesterol-lowering agents regulate radiation sensitivity of inflammatory breast cancer (IBC) cell lines in vitro and are associated with less radiation resistance among IBC patients who undergo postmastectomy radiation. We hypothesized that decreasing IBC cellular cholesterol induced by treatment with lipoproteins would increase radiation sensitivity. Here, we examined the impact of specific transporters of cholesterol (ie lipoproteins) on the responses of IBC cells to self-renewal and to radiation in vitro and on clinical outcomes in IBC patients. Methods and Materials Two patient-derived IBC cell lines, SUM 149 and KPL4, were incubated with low-density lipoproteins (LDL), very-low-density lipoproteins (VLDL), or high-density lipoproteins (HDL) for 24 hours prior to irradiation (0–6 Gy) and mammosphere formation assay. Cholesterol panels were examined in a cohort of patients with primary IBC diagnosed between 1995 and 2011 at MD Anderson Cancer Center. Lipoprotein levels were then correlated to patient outcome, using the log rank statistical model, and examined in multivariate analysis using Cox regression. Results VLDL increased and HDL decreased mammosphere formation compared to untreated SUM 149 and KPL4 cells. Survival curves showed enhancement of survival in both of the IBC cell lines when pretreated with VLDL and, conversely, radiation sensitization in all cell lines when pretreated with HDL. In IBC patients, higher VLDL values (>30 mg/dL) predicted a lower 5-year overall survival rate than normal values (hazard ratio [HR] = 1.9 [95% confidence interval [CI]: 1.05–3.45], P=.035). Lower-than-normal patient HDL values (<60 mg/dL) predicted a lower 5-year overall survival rate than values higher than 60 mg/dL (HR = 3.21 [95% CI: 1.25–8.27], P=.015). Conclusions This study discovered a relationship among the plasma levels of lipoproteins, overall patient response, and radiation resistance in IBC patients and IBC patient-derived cell lines. A more expansive study is needed to verify these observations.

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