Selected 2008 Inflammatory Breast Cancer published research.
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Van Laere, S., et al. (2008). Relapse-free survival in breast cancer patients is associated with a gene expression signature characteristic for inflammatory breast cancer. Clinical Cancer Research, 14(22), 7452-60. Abstract below, free full text may be found at link above.
We hypothesize that a gene expression profile characteristic for inflammatory breast cancer (IBC), an aggressive form of breast cancer associated with rapid cancer dissemination and poor survival, might be related to tumor aggressiveness in non-IBC (nIBC). EXPERIMENTAL DESIGN: RNA from 17 IBC samples and 40 nIBC samples was hybridized onto Affymetrix chips. A gene signature predictive of IBC was identified and applied onto 1,157 nIBC samples with survival data of 881 nIBC samples. Samples were classified as IBC-like or nIBC-like. The IBC signature classification was compared with the classifications according to other prognostically relevant gene signatures and clinicopathologic variables. In addition, relapse-free survival (RFS) was compared by the Kaplan-Meyer method. RESULTS: Classification according to the IBC signature is significantly (P < 0.05) associated with the cell-of-origin subtypes, the wound healing response, the invasive gene signature, the genomic grade index, the fibroblastic neoplasm signature, and the 70-gene prognostic signature. Significant associations (P < 0.01) were found between the IBC signature and tumor grade, estrogen receptor status, ErbB2 status, and patient age at diagnosis. Patients with an IBC-like phenotype show a significantly shorter RFS interval (P < 0.05). Oncomine analysis identified cell motility as an important concept linked with the IBC signature. CONCLUSIONS: We show that nIBC carcinomas having an IBC-like phenotype have a reduced RFS interval. This suggests that IBC and nIBC show comparable phenotypic traits, for example augmented cell motility, with respect to aggressive tumor cell behavior. This observation lends credit to the use of IBC to study aggressive tumor cell behavior.
Medina, PJ., & Goodin, S. (2008). Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clinical Therapeutics, 30(8), 1426-47. Abstract below, free full text not available.
BACKGROUND: Lapatinib, the first dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, was approved by the US Food and Drug Administration (FDA) in 2007. It is indicated for use in combination with capecitabine for the treatment of patients with advanced breast cancer or metastatic breast cancer (MBC) whose tumors overexpress HER2 (ErbB2) and who have received previous treatment that included an anthracycline, a taxane, and trastuzumab. OBJECTIVE: This review summarizes the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of lapatinib, and its current and potential role in the treatment of breast cancer and other malignancies. METHODS: Relevant English-language publications were identified through searches of MEDLINE (1966-May 2008),the American Society of Clinical Oncology abstracts database (2000-2007), abstracts from the San Antonio Breast Cancer Symposium (2005-2007), and the FDA Web site (January 2008). Search terms included lapatinib, GW572016, HER2, EGFR, receptor tyrosine kinase, dual-receptor blockade, adverse events, and clinical trials. RESULTS: The T(max) of lapatinib after oral administration is 3 to 4 hours. Dividing the dose or administering it with food, particularly a high-fat meal, increases the AUC >2-fold. Lapatinib is metabolized primarily by the cytochrome P450 3A4 isozyme, with 1 metabolite remaining active against EGFR but not HER2. Due to drug accumulation, the t(1/2) of lapatinib is 24 hours with continuous dosing. In a Phase III trial comparing lapatinib and capecitabine with capecitabine alone in women with HER2-positive, locally advanced breast cancer or MBC that had progressed after treatment with an anthracycline, a taxane, and trastuzumab, the combination of lapatinib and capecitabine was associated with a numeric improvement in response rate compared with capecitabine alone (22% vs 14%, respectively; P = NS) and a significant increase in time to progression (6.2 vs 4.3 months; hazard ratio = 0.57; 95% CI, 0.43-0.77; P < 0.001). Lapatinib has been reported to have antitumor activity in Phase II trials when used as first-line therapy for MBC, in patients with inflammatory breast cancer, and in patients with central nervous system metastases. Phase II trials in other solid tumor types found modest activity. The approved dosing of lapatinib is 1,250 mg PO QD given continuously in combination with capecitabine 2,000 mg/m(2) daily administered in 2 divided doses on days 1 to 14 of a 21-day cycle. The most common clinical toxicities of all grades associated with lapatinib used in combination with capecitabine in the pivotal clinical trial were diarrhea (65%), hand-foot syndrome (53%), nausea (44%), rash (29%), and fatigue (24%). Cardiac toxicity appears to be less frequent with lapatinib than with trastuzumab. CONCLUSIONS: Lapatinib is a dual inhibitor of the EGFR and HER2 tyrosine kinases. It is approved by the FDA for use in combination with capecitabine for the treatment of HER2-positive MBC that has progressed with standard treatment. In clinical trials, this combination was associated with a significant improvement in the time to progression in patients with MBC. Lapatinib’s efficacy in other malignancies that overexpress EGFR and/or HER2 is under evaluation.
Yang, SX., et al. (2008). Gene expression profile and angiogenic marker correlates with response to neoadjuvant bevacizumab followed by bevacizumab plus chemotherapy in breast cancer. Clinical Cancer Research, 14(18), 5893-9. Abstract below, free full text may be found at link above.
To identify biomarkers and gene expression profile signatures to distinguish patients with partial response (PR) from those with stable disease (SD) and progressive disease (PD). EXPERIMENTAL DESIGN: Twenty patients with inflammatory breast cancer and one patient with locally advanced breast cancer received one cycle of bevacizumab followed by six cycles of bevacizumab plus docetaxel-doxorubicin before surgery. Baseline angiogenic/tumor markers were examined by immunohistochemistry and gene expression profiles were measured by Agilent Whole Human Genome arrays. All were assessed for clinical response. RESULTS: Fourteen patients (67%, 95% confidence interval, 43-85.4%) had PR, five had SD, and two had PD. Expression of CD31 and platelet-derived growth factor receptor-beta (PDGFR-beta) in the tumor vasculature by immunohistochemistry was significantly associated with response (PR versus SD/PD; CD31 median, 33.5 versus 13.2; P = 0.0004; PDGFR-beta median, 5.9 versus 0.6; P = 0.01). Tumor VEGF-A showed a trend towards association with response (2.65 versus 0.25; P = 0.04). pVEGFR2(Y996), pVEGFR2(Y951), MVD, Ki67, apoptosis, grade, ER, HER-2/neu, and p53 were not associated with response. Twenty-six of 1,339 Gene Ontology (GO) classes at the gene transcriptional level were differentially expressed between patients with PR and SD/PD (P < 0.005). Representative significant GO classes include spindle (11 genes; P = 0.001), vascular endothelial growth factor receptor activity including PDGFR-beta (5 genes; P = 0.002), and cell motility including CD31 (80 genes; P = 0.005). CONCLUSIONS: Baseline CD31, PDGFR-beta, and GO classes for vascular endothelial growth factor receptor activity and mitosis were significantly associated with response to bevacizumab followed by bevacizumab plus chemotherapy.
Nogi, H., et al. (2008). The predictive value of PgR and HER-2 for response to primary systemic chemotherapy in inflammatory breast cancer. International Journal of Clinical Oncology, 13(4), 340-4. Abstract below, free full text not available.
BACKGROUND: Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer. We examined the relationship between clinicopathological factors and clinical response to primary systemic chemotherapy (PSC) and outcome. METHODS: Twenty-five patients with IBC were examined. Twelve patients received an anthracycline-based regimen, and 13 patients received an anthracycline-and a taxane-containing regimen as PSC. The expression of hormone receptors and human epidermal growth factor receptor-2 (HER-2) was determined by immunohistochemistry. RESULTS: The overall clinical response rate was 64.0%. Clinical response to PSC was higher in patients with progesterone receptor (PgR)-positive (P = 0.01) and HER-2-negative (P = 0.03) tumors. Patients with fewer than ten involved axillary lymph nodes (P = 0.01 and P = 0.02, respectively) and with a clinical response to PSC (P = 0.02 and P = 0.01, respectively) showed better distant disease-free survival and overall survival. CONCLUSION: In patients with IBC, PgR-positive and HER-2-negative tumors are more sensitive to anthracycline-based PSC. Patients with extensive residual tumor (ten or more lymph-nodes involved, no response to PSC) after PSC had unfavorable prognoses.
Xiao, Y., et al. (2008). The lymphovascular embolus of inflammatory breast cancer expresses a stem cell-like phenotype. The American Journal of Pathology, 173(2), 561-74. Abstract below, free full text may be found at link above.
Inflammatory breast carcinoma (IBC) is a particularly lethal form of breast cancer characterized by exaggerated lymphovascular invasion, which is a phenotype recapitulated in our human xenograft MARY-X. MARY-X generated spheroids in vitro that resemble the embryonal blastocyst. Because of the resemblance of the spheroids to the embryonal blastocyst and their resistance to traditional chemotherapy/radiotherapy, we hypothesized that the spheroids expressed a stem cell-like phenotype. MARY-X spheroids expressed embryonal stem cell markers including stellar, rex-1, nestin, H19, and potent transcriptional factors, oct-4, nanog, and sox-2, which are associated with stem cell self-renewal and developmental potential. Most importantly, MARY-X spheroids expressed a cancer stem cell profile characterized by CD44(+)/CD24(-/low), ALDH1, and most uniquely, CD133. A significant percentage of single cells of MARY-X exhibited distinct proliferative and morphogenic potencies in vitro. As few as 100 cells derived from single-cell clonogenic expansion were tumorigenic with recapitulation of the IBC phenotype. Prototype stem cell signaling pathways such as notch3 were active in MARY-X. The stem cell phenotype exhibited by MARY-X also was exhibited by the lymphovascular emboli of human IBC cases independent of their molecular subtype. This stem cell-like phenotype may contribute to the aggressive nature of IBC but also may lend itself to selective targeting.
Renz, DM., et al. (2008). Magnetic resonance imaging of inflammatory breast carcinoma and acute mastitis. a comparative study. European Radiology, 18(11), 2370-80. Abstract below, free full text not available.
The aim of this study was to evaluate the potential of magnetic resonance mammography (MRM) to distinguish inflammatory breast carcinomas (IBC) from acute mastitis (AM). This study compared MRM examinations of two selected groups of patients: 48 subjects with IBC and 42 patients with AM. No statistical differences were revealed between the two groups for morphology of masses and of non-mass-like enhancement, breast enlargement, diffuse skin thickening, abnormal nipple configuration, prominent vessels, and also for cutaneous/subcutaneous, perimamillar and diffuse oedema. However, initial and postinitial dynamic characteristics significantly differed between the two groups (p < 0.001). In IBC, more masses with a greater average size were detected (p < 0.05). The following morphological criteria were also observed more often in IBC (p < 0.05): T2-hypointensity of masses (77.5%/18.2%), blooming sign (62.5%/31.8%), infiltration of pectoralis major muscle (interruption of fat plane: 54.2%/16.7%; pathological enhancement: 33.3%/7.1%), perifocal (66.7%/33.3%), prepectoral (72.9%/31.0%) and intramuscular pectoral oedema (41.7%/7.1%). The main localisation of AM was subareolar, of IBC central or dorsal (p < 0.001). The discrimination between AM and IBC remains a diagnostic challenge because of overlapping imaging features. However, the combination of multiple dynamic and morphological MRM criteria seems to have the potential for a differential diagnosis.
Dawood, S., et al. (2008). Prognostic significance of HER-2 status in women with inflammatory breast cancer. Cancer, 112(9), 1905-11. Abstract below, free full text may be found at link above.
Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer with poorly understood prognostic variables. The purpose of this study was to define the prognostic impact of HER-2 status on survival outcomes of patients with IBC. METHODS: In all, 179 patients with IBC, diagnosed between 1989 and 2005, with known HER-2 status, and treated with an anthracycline-based chemotherapy regimen without trastuzumab, were included in the analysis. Patients with HER-2-positive disease who received trastuzumab at the time of disease recurrence were included. Survival outcomes were estimated by the Kaplan-Meier product limit method and compared across groups using the log-rank statistic. A Cox proportional hazards model was fitted to determine the association of survival outcomes with HER-2 status after adjusting for patient and tumor characteristics. RESULTS: A total of 111 patients (62%) had HER-2-negative disease and 68 (38%) had HER-2-positive disease. The median follow-up among all patients was 35 months. At the time of the analysis, 62 patients (55.9%) with HER-2-negative disease and 42 patients (61.8%) with HER-2-positive disease had a recurrence. Thirty-one patients (73.8%) with HER-2-positive disease who had a disease recurrence went on to receive trastuzumab. On univariate analysis, no statistically significant difference was observed for either recurrence-free survival (P = .75) or overall survival (P = .24) between patients who had HER-2-positive disease and those who had HER-2-negative disease. In a multivariate model, HER-2 status did not appear to significantly affect recurrence-free survival (hazards ratio [HR] of 0.75; 95% confidence interval [95% CI], 0.46-1.22 [P = .241]). In the multivariate model, patients with HER-2-positive disease had a decreased hazard of death (HR of 0.56; 95% CI, 0.34-0.93 [P = .024]) compared with patients with HER-2-negative disease. CONCLUSIONS: HER-2 status, in the absence of trastuzumab, did not appear to significantly affect recurrence-free survival. After adjusting for other characteristics, the addition of trastuzumab in the metastatic setting significantly improved survival in the HER-2-positive group above and beyond that of the HER-2-negative group. This gives us further insight into the biology of this aggressive disease and underlines the major effect of targeted intervention.
Lerebours, F., et al. (2008). NF-kappa B genes have a major role in inflammatory breast cancer. BMC Cancer, 8(41). Abstract below, free full text may be found at link above.
BACKGROUND: IBC (Inflammatory Breast cancer) is a rare form of breast cancer with a particular phenotype. New molecular targets are needed to improve the treatment of this rapidly fatal disease. Given the role of NF-kappaB-related genes in cell proliferation, invasiveness, angiogenesis and inflammation, we postulated that they might be deregulated in IBC. METHODS: We measured the mRNA expression levels of 60 NF-kappaB-related genes by using real-time quantitative RT-PCR in a well-defined series of 35 IBCs, by comparison with 22 stage IIB and III non inflammatory breast cancers. Twenty-four distant metastases of breast cancer served as “poor prognosis” breast tumor controls. RESULTS: Thirty-five (58%) of the 60 NF-kappaB-related genes were significantly upregulated in IBC compared with non IBC. The upregulated genes were NF-kappaB genes (NFKB1, RELA, IKBKG, NFKBIB, NFKB2, REL, CHUK), apoptosis genes (MCL1L, TNFAIP3/A20, GADD45B, FASLG, MCL1S, IER3L, TNFRSF10B/TRAILR2), immune response genes (CD40, CD48, TNFSF11/RANKL, TNFRSF11A/RANK, CCL2/MCP-1, CD40LG, IL15, GBP1), proliferation genes (CCND2, CCND3, CSF1R, CSF1, SOD2), tumor-promoting genes (CXCL12, SELE, TNC, VCAM1, ICAM1, PLAU/UPA) or angiogenesis genes (PTGS2/COX2, CXCL1/GRO1). Only two of these 35 genes (PTGS2/COX2 and CXCL1/GRO1)were also upregulated in breast cancer metastases. We identified a five-gene molecular signature that matched patient outcomes, consisting of IL8 and VEGF plus three NF-kappaB-unrelated genes that we had previously identified as prognostic markers in the same series of IBC. CONCLUSION: The NF-kappaB pathway appears to play a major role in IBC, possibly contributing to the unusual phenotype and aggressiveness of this form of breast cancer. Some upregulated NF-kappaB-related genes might serve as novel therapeutic targets in IBC.
Johnston, S., et al. (2008). Phase IIstudy of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (her-2) in advanced inflammatory breast cancer with lapatinib monotherapy. Journal of Clinical Oncology, 26(7), 1066-72. Abstract below, free full text not available.
PURPOSE: Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity. PATIENTS AND METHODS: Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2-overexpressing [HER-2+]) or B(HER-2-/EGFR+) and fresh pretreatment tumor biopsies were collected. RESULTS: Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib. CONCLUSION: Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2-, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC.
Renz , DM., et al. (2008). Inflammatory breast carcinoma in magnetic resonance imaging: a comparison with locally advanced breast cancer. Academic Radiology, 15(2), 209-21. Abstract below, free full text not available.
Although inflammatory breast carcinoma (IBC) accounts for 1%-4% of all breast cancer cases, the appearance of this highly malignant tumor in magnetic resonance imaging (MRI) is still not well characterized. The aim of this study was to identify typical imaging features of IBC in comparison with noninflammatory locally advanced breast carcinoma (LABC). MATERIALS AND METHODS: MRIs of 48 patients with IBC were compared with an equivalent cohort of 52 subjects with LABC. Age and histopathologic subtype were equivalent between the two groups. To delineate characteristic features, a multitude of dynamic and morphologic parameters were evaluated using T1- and T2-weighted sequences. RESULTS: No significant differences of prevalences could be found for the following criteria: dynamic tumor signal characteristics, prominent vessels, perifocal edema, axillary lymph node involvement, morphology of focal masses, and morphologic pattern of non-mass like enhancement. Otherwise, the quantity of focal masses and the spatial distribution of the tumoral infiltration significantly differed between the two cancer groups. The following parameters occurred more frequently in the IBC cases: edema (cutaneous/subcutaneous 81.3%, perimamillar 70.8%, diffuse 89.6%, prepectoral 72.9%, intramuscular pectoral 41.7%), thickening (75.0%) and pathologic enhancement (60.4%) of Cooper’s ligaments, skin thickening (83.3%), punched-out sign (initially strong, focal increase of some dermal or subcutaneous parts followed by slow-continuous enhancement of the surrounding skin; 56.3%). CONCLUSIONS: Inflammatory breast carcinoma seems to represent a specific biological entity resulting in typical MRI characteristics. Some of the parameters are supposed to visualize the characteristic extensive lymphovascular infiltration and therefore may improve the diagnosis of IBC.
Aird, KM., et al. (2008). Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with x-linked inhibitor of apoptosis protein expression. Molecular Cancer Therapeutics, 7(1), 38-47. Abstract below, free full text may be found at link above.
Inflammatory breast cancer (IBC) patients show poor survival and a significant incidence of epidermal growth factor receptor-2 (ErbB2) overexpression. A distinct mechanism involving increased expression of X-linked inhibitor of apoptosis protein (XIAP) and survivin, key members of the inhibitor of apoptosis protein (IAP) family, was observed post-trastuzumab (an ErbB2 monoclonal antibody) treatment in an ErbB2-overexpressing, estrogen receptor negative, IBC cellular model, SUM190PT, isolated from a primary IBC tumor. In contrast, a decrease in the IAP expression was observed in the non-IBC, ErbB2-overexpressing SKBR3 cells in which trastuzumab treatment also decreased p-AKT and cell viability. Further, in SUM190PT cells, therapeutic sensitivity to GW583340 (a dual epidermal growth factor receptor/ErbB2 kinase inhibitor) corresponded with XIAP down-regulation and abrogation of XIAP inhibition on active caspase-9 release. Specific small interfering RNA-mediated XIAP inhibition in combination with trastuzumab caused decrease in inactive procaspase-9 and inhibition of p-AKT corresponding with 45% to 50% decrease in cell viability in the SUM190PT cells, which have high steady-state p-AKT levels. Further, embelin, a small-molecule inhibitor that abrogates binding of XIAP to procaspase-9, caused significant decrease in SUM190PT viability. However, embelin in combination with trastuzumab failed to affect SUM190PT viability because it has no direct effect on XIAP, which is induced by trastuzumab treatment. These data have identified a novel functional link between ErbB2 signaling and antiapoptotic pathway mediated by XIAP. Blockade of the IAP antiapoptotic pathway alone or in combination would be an attractive strategy in IBC therapy.
Yang, WT., et al. (2008). Inflammatory breast cancer: PET/CT, MRI, mammography, and sonography findings. Breast Cancer Research and Treatment, 109(3), 417-26. Abstract below, free full text not available.
PURPOSE: To describe the role of Positron Emission Tomography/Computed Tomography (PET/CT), Magnetic Resonance Imaging (MRI), sonography, and mammography in patients with inflammatory breast cancer (IBC). MATERIALS AND METHODS: Patients who had been newly diagnosed with IBC and who had undergone mammography, sonography, MRI, PET/CT, or a combination of these were included in this study. The visibility of breast parenchymal lesion (BPLs), skin abnormalities, regional (axillary, supraclavicular, or internal mammary) nodal disease, and distant metastatic disease was documented with the imaging techniques. RESULTS: Eighty patients (median age, 51 years, [range, 25-78 years]) were included in this study: 75 (94%) had undergone mammography, 76 (95%) sonography, 33 (41%) MRI, and 24 (30%) PET/CT. A primary BPL was found in 60 patients (80%) on mammography (mass or calcifications), 72 (95%) on sonography (mass or architectural distortion), 23 (96%) on PET/CT (hypermetabolic BPL), and 33 (100%) on MRI (enhancing BPL). Regional axillary nodal disease was found in 74 patients (93%) by histologic or cytologic examination, in 71 patients (93%) on sonography, in 21 (88%) on PET/CT, in 29 (88%) on MRI, and in 34 (45%) on mammography. Distant metastases in the bone, liver, and contralateral lymph nodes were diagnosed in nine patients (38%) on PET/CT. CONCLUSION: MRI was the most accurate imaging technique in detecting a primary BPL in IBC patients. Sonography can be useful in diagnosing regional nodal disease. PET/CT provides additional information on distant metastasis, and it should be considered in the initial staging of IBC.