Selected 2013 Inflammatory Breast Cancer published research.
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Saigal, K., et al. (2013). Risk factors for locoregional failure in patients with inflammatory breast cancer treated with trimodality therapy. Clinical Breast Cancer, 13(5), 335-43. doi: 10.1016/j.clbc.2013.04.002. Abstract below, free full text not available.
To compare patterns of local and regional failure between patients with inflammatory breast cancer (IBC) and non-IBC in patients treated with trimodality therapy.
MATERIALS AND METHODS:
We reviewed records of 463 patients with stage II/III breast cancer, including IBC, who completed trimodality therapy from January 1999 to December 2009.
The median follow-up was 46.3 months (range, 4-152 months). Clinical stage was 29.4% (n = 136) II, 56.4% (n = 261) non-IBC III, 14.2% (n = 66) IBC, 30.5% (n = 141) cN0/Nx, and 69.5% (n = 322) N1-N3c. All the patients received neoadjuvant therapy and mastectomy (98%, n = 456 with axillary dissection), and all had postmastectomy radiation therapy to the chest wall with or without supraclavicular nodes (82.5%, n = 382) with or without axilla (6%, n = 28). The median chest wall dose was 60.4 Gy. Patients with IBC presented with larger tumors (P < .001) and exhibited a poorer response to neoadjuvant therapy: after surgery, fewer patients with IBC were ypN0 (P = .003) and more had = 4 positive nodes (P < .001). Four-year cumulative incidence of locoregional recurrence was 5.9%, with 25 locoregional events, 9 of which had a regional component. On multivariate analysis, triple-negative disease (hazard ratio [HR] 7.75, P < .0001) and residual pathologic nodes (HR 7.10, P < .001) were associated with an increased risk of locoregional recurrence, but IBC was not. However, on multivariate analysis, the 4-year cumulative incidence of regional recurrence specifically was significantly higher in IBC (HR 9.87, P = .005).
In this cohort of patients who completed trimodality therapy, the patients with IBC were more likely to have residual disease in the axilla after neoadjuvant therapy and were at greater risk of regional recurrence. Future study should focus on optimizing regional nodal management in IBC.
Van Laere, SJ., et al. (2013). Uncovering the molecular secrets of inflammatory breast cancer biology: an integrated analysis of three distinct affymetrix gene expression datasets. Clinical Cancer Research, 19(17), 4685-96. doi: 10.1158/1078-0432.CCR-12-2549. Abstract below, free full text not available.
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 3 Affymetrix expression data sets collected through the World IBC Consortium allowing us to interrogate the molecular profile of IBC using the largest series of IBC samples ever reported.
Affymetrix profiles (HGU133-series) from 137 IBC patients and 252 non-IBC patients (nIBC) were analyzed using unsupervised and supervised techniques. Samples were classified according 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.
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 TGFß signaling in IBC.
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 TGFß signaling, potentially explaining the metastatic potential of IBC tumor cells in an unexpected manner.
Fernandez, SV., et al. (2013). Inflammatory breast cancer (IBC): clues for targeted therapies. Breast Cancer Research and Treatment, 140(1), 23-33. doi: 10.1007/s10549-013-2600-4.
Inflammatory breast cancer (IBC) is the most aggressive type of advanced breast cancer characterized by rapid proliferation, early metastatic development and poor prognosis. Since there are few preclinical models of IBC, there is a general lack of understanding of the complexity of the disease. Recently, we have developed a new model of IBC derived from the pleural effusion of a woman with metastatic secondary IBC. FC-IBC02 cells are triple negative and form clusters (mammospheres) in suspension that are strongly positive for E-cadherin, ß-catenin and TSPAN24, all adhesion molecules that play an important role in cell migration and invasion. FC-IBC02 cells expressed stem cell markers and some, but not all of the characteristics of cells undergoing epithelial mesenchymal transition (EMT). Breast tumor FC-IBC02 xenografts developed quickly in SCID mice with the presence of tumor emboli and the development of lymph node and lung metastases. Remarkably, FC-IBC02 cells were able to produce brain metastasis in mice on intracardiac or intraperitoneal injections. Genomic studies of FC-IBC02 and other IBC cell lines showed that IBC cells had important amplification of 8q24 where MYC, ATAD2 and the focal adhesion kinase FAK1 are located. MYC and ATAD2 showed between 2.5 and 7 copies in IBC cells. FAK1, which plays important roles in anoikis resistance and tumor metastasis, showed 6-4 copies in IBC cells. Also, CD44 was amplified in triple-negative IBC cells (10-3 copies). Additionally, FC-IBC02 showed amplification of ALK and NOTCH3. These results indicate that MYC, ATAD2, CD44, NOTCH3, ALK and/or FAK1 may be used as potential targeted therapies against IBC.
Schairer, C., et al. (2013). Assessment of diagnosis of inflammatory breast cancer cases at two cancer centers in Egypt and Tunisia. Cancer Medicine, 2(2), 178-84. doi: 10.1002/cam4.48. Abstract below, free full text available at link in article title.
The diagnosis of inflammatory breast cancer (IBC) is largely clinical and therefore inherently somewhat subjective. The objective of this study was to evaluate the diagnosis of IBC at two centers in North Africa where a higher proportion of breast cancer is diagnosed as IBC than in the United States (U.S.). Physicians prospectively enrolled suspected IBC cases at the National Cancer Institute (NCI) – Cairo, Egypt, and the Institut Salah Azaiz (ISA), Tunisia, recorded extent and duration of signs/symptoms of IBC on standardized forms, and took digital photographs of the breast. After second-level review at study hospitals, photographs and clinical information for confirmed IBC cases were reviewed by two U.S. oncologists. We calculated percent agreement between study hospital and U.S. oncologist diagnoses. Among cases confirmed by at least one U.S. oncologist, we calculated median extent and duration of signs and Spearman correlations. At least one U.S. oncologist confirmed the IBC diagnosis for 69% (39/50) of cases with photographs at the NCI-Cairo and 88% (21/24) of cases at the ISA. All confirmed cases had at least one sign of IBC (erythema, edema, peau d’orange) that covered at least one-third of the breast. The median duration of signs ranged from 1 to 3 months; extent and duration of signs were not statistically significantly correlated. From the above-mentioned outcomes, it can be concluded that the diagnosis of a substantial proportion
of IBC cases is unambiguous, but a subset is difficult to distinguish from other types of locally advanced breast cancer. Among confirmed cases, the extent of signs was not related to delay in diagnosis.
Williams, K., et al. (2013). Quantitative high-throughput efficacy profiling of approved oncology drugs in Inflammatory Breast Cancer models of acquired drug resistance and re-sensitization. Cancer Letters, 337(1), 77-89. doi: 10.1016/j.canlet.2013.05.017.Abstract below, free full text not available.
Although there is no standard treatment protocol for inflammatory breast cancer (IBC), multi-modality treatment has improved survival. In this study we profiled the NCI approved oncology drug set in a qHTS format to identify those that are efficacious in basal type and ErbB2 overexpressing IBC models. Further, we characterized the sensitivity of an acquired therapeutic resistance model to the oncology drugs. We observed that lapatinib-induced acquired resistance in SUM149 cells led to cross-resistance to other targeted- and chemotherapeutic drugs. Removal of the primary drug to which the model was developed led to re-sensitization to multiple drugs to a degree comparable to the parental cell line; this coincided with the cells regaining the ability to accumulate ROS and reduced expression of anti-apoptotic factors and the antioxidant SOD2. We suggest that our findings provide a unique IBC model system for gaining an understanding of acquired therapeutic resistance and the effect of redox adaptation on anti-cancer drug efficacy.
Champion, L., et al. (2013). 18F-FDG PET/CT imaging versus dynamic contrast-enhanced CT for staging and prognosis of Inflammatory Breast Cancer. European Journal of Nuclear Medicine and Molecular Imaging, 40(8), 1206-13. doi: 10.1007/s00259-013-2405-z. Abstract below, free full text not available.
Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer with a poor prognosis. Locoregional staging is based on dynamic contrast-enhanced (DCE) CT or MRI. The aim of this study was to compare the performances of FDG PET/CT and DCE CT in locoregional staging of IBC and to assess their respective prognostic values.
The study group comprised 50 women (median age: 51 ± 11 years) followed in our institution for IBC who underwent FDG PET/CT and DCE CT scans (median interval 5 ± 9 days). CT enhancement parameters were net maximal enhancement, net early enhancement and perfusion.
The PET/CT scans showed intense FDG uptake in all primary tumours. Concordance rate between PET/CT and DCE CT for breast tumour localization was 92 %. No significant correlation was found between SUVmax and CT enhancement parameters in primary tumours (p > 0.6). PET/CT and DCE CT results were poorly correlated for skin infiltration (kappa = 0.19). Ipsilateral foci of increased axillary FDG uptake were found in 47 patients (median SUV: 7.9 ± 5.4), whereas enlarged axillary lymph nodes were observed on DCE CT in 43 patients. Results for axillary node
involvement were fairly well correlated (kappa = 0.55). Nineteen patients (38 %) were found to be metastatic on PET/CT scan with a significant shorter progression-free survival than patients without distant lesions (p = 0.01). In the primary tumour, no statistically significant difference was observed between high and moderate tumour FDG uptake on survival, using an SUVmax cut-off of 5 (p = 0.7 and 0.9), or between high and low tumour enhancement on DCE CT (p > 0.8).
FDG PET/CT imaging provided additional information concerning locoregional involvement to that provided by DCE CT on and allowed detection of distant metastases in the same whole-body procedure. Tumour FDG uptake or CT enhancement parameters were not correlated and were not found to have any prognostic value
Nokes, B., et al. (2013). In vitro assessment of the inflammatory breast cancer cell line SUM 149: Discovery of 2 single nucleotide polymorphisms in the RNase L gene. Journal of Cancer, 4(2), 104-16. Abstract below, free full text available at link in article title.
Background: Inflammatory breast cancer (IBC) is a rare, highly aggressive form of breast cancer. The mechanism of IBC carcinogenesis remains unknown. We sought to evaluate potential genetic risk factors for IBC and whether or not the IBC cell lines SUM149 and SUM190 demonstrated evidence of viral infection. Methods: We performed single nucleotide polymorphism (SNP) genotyping for 2 variants of the ribonuclease (RNase) L gene that have been correlated with the risk of prostate cancer due to a possible viral etiology. We evaluated dose-response to treatment with interferon-alpha (IFN-a); and
assayed for evidence of the putative human mammary tumor virus (HMTV, which has been implicated in IBC) in SUM149 cells. A bioinformatic analysis was performed to evaluate expression of RNase L in IBC and non-IBC.Results: 2 of 2 IBC cell lines were homozygous for RNase L common missense variants 462 and 541; whereas 2 of 10 non-IBC cell lines were homozygous positive for the 462 variant (p= 0.09) and 0 of 10 non-IBC cell lines were homozygous positive for the 541 variant (p = 0.015). Our real-time polymerase chain reaction (RT-PCR) and Southern blot analysis for sequences of HMTV revealed no evidence of the putative viral genome.Conclusion: We discovered 2 SNPs in the RNase L gene that were homozygously present in IBC cell lines. The 462 variant was absent in non-IBC lines. Our discovery of these SNPs present in IBC cell lines suggests a possible biomarker for risk of IBC. We found no evidence of HMTV in SUM149 cells. A query of a panel of human IBC and non-IBC samples showed no difference in RNase L expression. Further studies of the RNase L 462 and 541 variants in IBC tissues are warranted to validate our in vitro findings.
El-Shinawi , M., et al. (2013). Human cytomegalovirus infection enhances NF-kB/p65 signaling in inflammatory breast cancer patients. PLoS One, 8(2), doi: 10.1371/journal.pone.0055755. Free full text available.
Human Cytomegalovirus (HCMV) is an endemic herpes virus that re-emerges in cancer patients enhancing oncogenic potential. Recent studies have shown that HCMV infection is associated with certain types of cancer morbidity such as glioblastoma. Although HCMV has been detected in breast cancer tissues, its role, if any, in the etiology of specific forms of breast cancer has not been investigated. In the present study we investigated the presence of HCMV infection in inflammatory breast cancer (IBC), a rapidly progressing form of breast cancer characterized by specific molecular signature. We screened for anti-CMV IgG antibodies in peripheral blood of 49 non-IBC invasive ductal carcinoma (IDC) and 28 IBC patients. In addition, we screened for HCMV-DNA in postsurgical cancer and non-cancer breast tissues of non-IBC and IBC patients. We also tested whether HCMV infection can modulate the expression and activation of transcriptional factor NF-kB/p65, a hallmark of IBC. Our results reveal that IBC patients are characterized by a statistically significant increase in HCMV IgG antibody titers compared to non-IBC patients. HCMV-DNA was significantly detected in cancer tissues than in the adjacent non-carcinoma tissues of IBC and IDC, and IBC cancer tissues were significantly more infected with HCMV-DNA compared to IDC. Further, HCMV sequence analysis detected different HCMV strains in IBC patients tissues, but not in the IDC specimens. Moreover, HCMV-infected IBC cancer tissues were found to be enhanced in NF-kB/p65 signaling compared to non-IBC patients. The present results demonstrated a correlation between HCMV infection and IBC. Etiology and causality of HCMV infection with IBC now needs to be rigorously examined.
Lerebours, F., et al. (2013). miRNA expression profiling of inflammatory breast cancer identifies a 5-miRNA signature predictive of breast tumor aggressiveness. International Journal of Cancer, doi: 10.1002/ijc.28171. Abstract below, free full text not available.
IBC (inflammatory breast cancer) is a rare but very aggressive form of breast cancer with a particular phenotype. The molecular mechanisms responsible for IBC remain largely unknown. In particular, genetic and epigenetic alterations specific to IBC remain to be identified. MicroRNAs, a class of small noncoding RNAs able to regulate gene expression, are deregulated in breast cancer and may therefore serve as tools for diagnosis and prediction. This study was designed to determine miRNA expression profiling (microRNAome) in IBC. Quantitative RT-PCR was used to determine expression levels of 804 miRNAs in a screening series of 12 IBC compared to 31 non-stage-matched non-IBC and 8 normal breast samples. The differentially expressed miRNAs were then validated in a series of 65 IBC and 95 non-IBC. From a set of 18 miRNAs of interest selected from the screening series, 13 were differentially expressed with statistical significance in the validation series of IBC compared to non-IBC. Among these, a 5-miRNA signature comprising miR-421, miR-486, miR-503, miR-720 and miR-1303 was shown to be predictive for IBC phenotype with an overall accuracy of 89%. Moreover, multivariate analysis showed that this signature was an independent predictor of poor Metastasis-Free Survival in non-IBC patients.
Nair, S., et al. (2013). Immunologic targeting of FOXP3 in inflammatory breast cancer cells. PLoS One, 8(1), doi: 10.1371/journal.pone.0053150. Free full text available.
The forkhead transcription factor FOXP3 is necessary for induction of regulatory T lymphocytes (Tregs) and their immunosuppressive function. We have previously demonstrated that targeting Tregs by vaccination of mice with murine FOXP3 mRNA-transfected dendritic cells (DCs) elicits FOXP3-specific T cell responses and enhances tumor immunity. It is clear that FOXP3 expression is not restricted to T-cell lineage and herein, using RT-PCR, flow cytometry, and western immunoblot we demonstrate for the first time that FOXP3 is expressed in inflammatory breast cancer (IBC) cells, SUM149 (triple negative, ErbB1-activated) and SUM190 (ErbB2-overexpressing). Importantly, FOXP3-specific T cells generated in vitro using human FOXP3 RNA-transfected DCs as stimulators efficiently lyse SUM149 cells. Interestingly, an isogenic model (rSUM149) derived from SUM149 with an enhanced anti-apoptotic phenotype was resistant to FOXP3-specific T cell mediated lysis. The MHC class I cellular processing mechanism was intact in both cell lines at the protein and transcription levels suggesting that the resistance to cytolysis by rSUM149 cells was not related to MHC class I expression or to the MHC class I antigen processing machinery in these cells. Our data suggest that FOXP3 may be an effective tumor target in IBC cells however increased anti-apoptotic signaling can lead to immune evasion.
Allenworth, JL., et al. (2013). Smac mimetic birinapant induces apoptosis and enhances trail potency in inflammatory breast cancer cells in an iap-dependent and tnf-?-independent mechanism. Breast Cancer Research and Treatment, 137(2), 359-71. Abstract below, free full text not available.
X-linked inhibitor of apoptosis protein (XIAP), the most potent mammalian caspase inhibitor, has been associated with acquired therapeutic resistance in inflammatory breast cancer (IBC), an aggressive subset of breast cancer with an extremely poor survival rate. The second mitochondria-derived activator of caspases (Smac) protein is a potent antagonist of IAP proteins and the basis for the development of Smac mimetic drugs. Here, we report for the first time that bivalent Smac mimetic Birinapant induces cell death as a single agent in TRAIL-insensitive SUM190 (ErbB2-overexpressing) cells and significantly increases potency of TRAIL-induced apoptosis in TRAIL-sensitive SUM149 (triple-negative, EGFR-activated) cells, two patient tumor-derived IBC models. Birinapant has high binding affinity (nM range) for cIAP1/2 and XIAP. Using isogenic SUM149- and SUM190-derived cells with differential XIAP expression (SUM149 wtXIAP, SUM190 shXIAP) and another bivalent Smac mimetic (GT13402) with high cIAP1/2 but low XIAP binding affinity (K (d) > 1 ?M), we show that XIAP inhibition is necessary for increasing TRAIL potency. In contrast, single agent efficacy of Birinapant is due to pan-IAP antagonism. Birinapant caused rapid cIAP1 degradation, caspase activation, PARP cleavage, and NF-?B activation. A modest increase in TNF-? production was seen in SUM190 cells following Birinapant treatment, but no increase occurred in SUM149 cells. Exogenous TNF-? addition did not increase Birinapant efficacy. Neutralizing antibodies against TNF-? or TNFR1 knockdown did not reverse cell death. However, pan-caspase inhibitor Q-VD-OPh reversed Birinapant-mediated cell death. In addition, Birinapant in combination or as a single agent decreased colony formation and anchorage-independent growth potential of IBC cells. By demonstrating that Birinapant primes cancer cells for death in an IAP-dependent manner, these findings support the development of Smac mimetics for IBC treatment.
Cristofanilli, M., et al. (2013). A randomized phase II study of lapatinib pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer. Breast Cancer Research and Treatment, 137(2), 471-82. doi: 10.1007/s10549-012-2369-x. Abstract below, free full text available at link in article title.
This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to receive lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrheaobserved with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily
monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38) and combination (n = 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade =3 adverse events (AEs) were more frequent in the combination arm (71 %) than in the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %, respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib + pazopanib (n = 38), and pazopanib (n = 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade =3 AEs were reported for 17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24, and 23 %, respectively. The lapatinib-pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib was confirmed in this population.
Groheux , D., et al. (2013). 18f-FDG-PET/CT in staging patients with locally advanced or inflammatory breast cancer: comparison to conventional staging. Journal of Nuclear Medicine, 54(1), 5-11. doi: 10.2967/jnumed.112.106864. Abstract below, free full text not available.
The prognosis of patients with locally advanced breast cancer (LABC) remains poor. We prospectively investigated the impact of (18)F-FDG PET/CT at initial staging in this clinical setting and compared PET/CT performance with that of conventional distant work-up. METHODS: During 60 mo, consecutive patients with LABC (clinical T4 or N2-N3 disease) underwent (18)F-FDG PET/CT. The yield was assessed in the whole group and separately for noninflammatory and inflammatory cancer. The performance of PET/CT was compared with that of a conventional staging approach including bone scanning, chest radiography, or dedicated CT and abdominopelvic sonography or contrast-enhanced CT. RESULTS: 117 patients with inflammatory (n = 35) or noninflammatory (n = 82) LABC were included. (18)F-FDG PET/CT confirmed N3 nodal involvement in stage IIIC patients and revealed unsuspected N3 nodes (infraclavicular, supraclavicular, or internal mammary) in 32 additional patients. Distant metastases were visualized on PET/CT in 43 patients (46% of patients with inflammatory carcinoma and 33% of those with noninflammatory LABC). Overall, (18)F-FDG PET/CT changed the clinical stage in 61 patients (52%). Unguided conventional imaging detected metastases in only 28 of the 43 patients classified M1 with PET/CT (65%). (18)F-FDG PET/CT outperformed conventional imaging for bone metastases, distant lymph nodes, and liver metastases, whereas CT was more sensitive for lung metastases. The accuracy in diagnosing bone lesions was 89.7% for planar bone scanning versus 98.3% for (18)F-FDG PET/CT. The accuracy in diagnosing lung metastases was 98.3% for dedicated CT versus 97.4% for (18)F-FDG PET/CT. CONCLUSION:(18)F-FDG PET/CT had the advantage of allowing chest, abdomen and bone to be examined in a single session. Almost all distant lesions detected by conventional imaging were depicted with PET/CT, which also showed additional lesions.