Features Of Inflammatory Breast Cancer Research Articles

P4-20-05: Inflammatory Breast Cancer: Comparison of Epidemiology, Biology, and Prognosis between Japan and the United States, a Hospital-Based Study.

Abstract Background: Inflammatory breast cancer (IBC) is a challenging disease characterized by low incidence, rapid progression, and poor survival. The epidemiology of IBC has been slow to emerge, given that the rarity of IBC makes large prospective clinical trials difficult. Compared to non-IBC, well-established features of IBC include a younger age of onset and lower frequency of hormone receptor positivity. Higher body mass index (BMI) is a purported risk factor. Previous reports also suggest that IBC is associated with more racial disparities, including incidence and age at diagnosis. The epidemiology of IBC in East Asia, however, has not been investigated. We performed a comparative study of IBC in Japan versus the United States to determine its epidemiologic and clinical features and to evaluate the differences in epidemiological factors between the two countries. Patients and Method: Patients who visited St. Luke's International hospital (SLIH) in Tokyo, Japan and The University of Texas MD Anderson Cancer Center (MDA) in Texas, USA between 2003 and 2009 were identified. Epidemiological and biological data were collected from electronic medical records. Patient and tumor characteristics were tabulated and stratified by hospital. Kaplan-Meier curves were created for survival estimates and log-rank test was used for cross-group comparisons. Cox proportional-hazard analysis was used to identify a subset of significant prognostic variables that related to overall survival. Result: 34 patients at SLIH and 531 patients at MDA were identified. Mean age at diagnosis was 52 years old (range, 32–81, SD, 10.8) and 50 years old (range, 22–87, SD, 11.6), respectively (P=0.476). Mean BMI was 22.9 kg/m2 (range, 17.3−30.5, SD 3.3 ) and 31.0 kg/m2 (range, 13.6−88.9, SD, 7.8) respectively (P<0.01). Clinical Staging was not significantly different; Stage IIIB 38.2%, Stage IIIC 26.5%, and Stage IV 32.4% at SLIH versus 48.6%, 23.7%, and 27.3% at MDA (P= 0.167). Estrogen receptor (ER) and progesterone receptor (PR) negative cases were, respectively, 50.0% and 64.7% at SLIH and 50.5% and 64.2% at MDA (ER, P= 0.935; PR, P=0.908). Her-2 over-expression cases were 38.2% at SLIH and 28.6% at MDA (P=0.174). A significant difference in nuclear grade was seen between SLIH and MDA: 20.6% at SLIH were Grade 3 versus 68.7% at MDA (P<0.01). Median overall survival at SLIH was 3.6 years versus 2.3 years at MDA (P=0.570). No prognostic factors were associated with overall survival. Conclusion: Though IBC at SLIH differed significantly from IBC at MDA by several epidemiologic and biologic factors, there was no significant difference in survival. To define the epidemiological, prognostic, and risk factors of IBC in Japan, as well as in the world, further studies are needed. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-20-05.

Sonographic Features of Inflammatory Breast Cancer

D t c s i Inflammatory breast carcinoma (IBC) is an aggressive form of invasive breast cancer characterized by diffuse erythema and edema (peau d’orange) of the breast, often without an underlying mass. IBC is usually a diagnosed on clinical examination with variable and nonspecific imaging findings. This aggressive cancer takes its name from the associated inflammatory-like symptoms that arise primarily from cancer cells blocking dermal lymphatics.1 The earliest documentation of IBC was in 1814, by Sir Charles Bell, who described a purple color on the skin over a breast tumor and shooting pains that were associated with the tumor.2 In 1924, Lee and Tannenbaum3 described “inflammatory breast cancer.” Dermal lymphatic invasion in IBC was described by Taylor and Meltzer in 1938.4 The possibilty of intraparenchymal lymphatic involvement being diagostic for IBC, in the absence of dermal lymphatic involveent, has also been suggested.5 According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, the incidence of IBC in 9 geographic areas of the United States was 6% among white women with breast cancer and 10% among black women with breast cancer between 1975 and 1981.6 Lower percentages were observed by other investigators, ranging from 0.5% to 1.3%.7-10 This difference may be related o the inclusion of locally advanced breast cancer cases mong IBC cases in the SEER database, resulting in an apparntly greater incidence of IBC. In a review of more recent EER data, from 1988 to 2000, investigators reported that BC comprised 2% of all breast malignancies.11 The incidence of IBC increased from 2.0% to 2.5% between 1988 and 1990 and 1997 and 1999, whereas the incidence of locally advanced breast cancers and non-T4 cancers decreased. The cause of the increase in the incidence of IBC is not known, but possible theories include heightened awareness, im-

MRI Features of Inflammatory Breast Cancer

The aim of this study was to evaluate the features of inflammatory breast carcinoma (IBC) on MRI compared with mammography and ultrasound and to better define the role of MRI in patients with this aggressive disease. A retrospective analysis was performed of patients with newly diagnosed IBC evaluated at a single institution between 2003 and 2008. Baseline MRI examinations were performed on a 1.5- or 3-T scanner using contrast-enhanced 3D T1-weighted gradient-echo sequences with parallel imaging. MRI findings were rated in accordance with the BI-RADS MRI lexicon established by the American College of Radiology. All patients underwent concomitant mammography and ultrasound examinations. Eighty women with a clinical diagnosis of IBC were included in the study (median age, 52 years; age range, 25-78 years). MRI detected a primary breast lesion in 78 of 80 symptomatic breasts (98%) compared with 53 of 78 (68%) with mammography (p < 0.0001) and 75 of 80 (94%) with ultrasound. Of the 78 breasts with a primary lesion, the most common MRI finding was a mass or multiple masses (57/78, 73%). Masses were frequently multiple, small, and confluent (47/57, 82%); mass margins, irregular (43/57, 75%); and internal enhancement pattern, heterogeneous (47/57, 82%). Kinetic analysis revealed a delayed washout pattern in 66 of 78 tumors (85%). MRI showed skin thickening in 74 of 80 breasts (93%), whereas mammography showed skin thickening in 56 of 78 breasts (72%). Multiple small, confluent, heterogeneously enhancing masses and global skin thickening are key MRI features of IBC that contribute to improved detection of a primary breast cancer and delineation of disease extent compared with mammography.

Molecular and epidemiological characteristics of inflammatory breast cancer in Algerian patients.

Inflammatory breast cancer (IBC) shows a high incidence in Tunisia and Egypt but epidemiological and molecular characteristics have not been described in Algeria. We compared 117 IBC and 59 non-IBC locally advanced breast cancers (LABC), for estrogen and progesterone receptors, HER2, and EGFR protein expression by immunohistochemistry, and HER2 gene amplification by chromogenic in situ hybridization. Demographic, clinico-pathological, and molecular variables were compared with chi-square and Fisher's exact tests to test for significance (P < 0.05, two-tailed). Overall survival (OS) and disease-free survival (DFS) were plotted using Kaplan-Meier curves and compared using the log-rank test. Tumor emboli were detected in 77% of IBC. Palpable masses were found in all LABC but only in 32% of IBC (P < 0.001). Recurrences were higher in LABC than in IBC (48 vs. 35%; P = 0.14) but OS was worse in IBC (68 vs. 71%; P = 0.06). There were no significant differences between IBC and LABC by demographics or by clinico-pathological parameters. The majority of IBC and LABC tumors were luminal A (62 and 64%), followed by basal (~18%, each), triple negative (~18%, each), and HER2+ (~10%, each) subtypes. In multivariate analyses, grade was associated with worse OS (P = 0.04), and DFS (P < 0.001) in IBC; chemo- and radio-therapy were associated with improved OS and DFS, respectively (P < 0.05 for each) in LABC. In conclusion, IBC in Algeria shows similar characteristics to IBC described for Egypt and Tunisia with subtle molecular differences. Current therapeutic treatments were not very effective in this population and new approaches are much needed.

Overcoming radiation resistance in inflammatory breast cancer.

The clinical-pathological features of inflammatory breast cancer include enrichment of factors that have been previously associated with radioresistant disease, including negative hormone receptor status and a phenotype enriched for relatively radioresistant breast cancer stem/progenitor cells. The risks and benefits of accelerated postmastectomy radiation treatment regimens in the multimodality management of inflammatory breast cancer were reviewed at the first International Inflammatory Breast Cancer Conference at The University of Texas M. D. Anderson Cancer Center. The biological basis for radiation resistance and strategies to radiosensitize these tumors were also presented. The prevalent basal phenotype of inflammatory breast cancer makes it an ideal clinical model to examine stem cell hypotheses, which the authors believe can help guide future trials to continue making incremental progress against this aggressive disease.

Proceedings of the First International Inflammatory Breast Cancer Conference

Inflammatory breast cancer (IBC) is the most aggressive and deadly form of breast cancer. The peculiar clinical presentation and relative low incidence compared with non-IBC breast cancer contributes to delays in diagnoses and, consequently, to the dismal prognosis of these patients. Moreover, the etiology and pathogenesis of IBC remain largely unknown and there are currently no approved treatments for this disease. With these premises, we felt there were compelling reasons to convene a meeting solely dedicated to IBC. In December 2008, the first International Inflammatory Breast Cancer Conference, organized by an international committee of expert physicians and scientists and hosted by The University of Texas M.D. Anderson Cancer Center, was held inHouston, Texas. An international group of nearly 300 healthcare professionals, researchers, and patient advocates from 17 countries gathered to participate in the day and a half conference. Fifty posters were presented representing the leading edge of epidemiological studies and clinical and basic science research. This supplement of the Cancer Journal gathers the scientific contributions presented by the participants at the meetings that were organized with the scope of 1) providing an in-depth overview of the disease for educational purposes and 2) highlighting new research findings. The manuscripts are presented in the sequence discussed at the meeting. The first session was devoted to summarizing the current understanding of IBC epidemiology. The disease has previously been reported to comprise up to 20% of new cases in Tunisia and North Africa, and Dr. Boussen’s manuscript reviews the data and hypothesis supporting such claims. Furthermore, we review the incidence in the Mediterranean regions and discuss the supporting data for viral etiopathogenetic hypotheses. Moreover, we open the debate related to the contribution of an ambiguous IBC definition to the proper classification in large databases such as the Tumor Registries. The subsequent section deals with the important aspects of clinical and pathological diagnosis and procedures used to support the most appropriate steps for tissue collections and pathological review. This subject introduces the current understanding of the peculiar biological features of IBC supported by data from gene profiling and biomarker analyses, some of which highlight the potential for IBC as a disease in which cancer stem cells represent a predominant population. The therapeutic approaches associated with this feature support the development of more effective targeted therapies. The data frommost recent research findings are presented as additional evidence of possible alternative therapeutic opportunities. Finally, we discuss the role of appropriate locoregional therapy (surgery and radiotherapy) in themultidisciplinarymanagement of the disease. In summary, we hope these proceedings can provide a valuable educational source for every clinical investigator that deals with women with breast cancer. In addition, several research topics have the potential to attract interest of bench investigators to improve the current understanding of the disease. We have not included in these proceedings the testimonials of IBC survivors and advocates that made the IBC conference unique and meaningful. They remain a constant reminder of the urgency of the work and the need for dedicated resources that will allow us to finally understand and cure this deadly disease.

Evaluation of a CXCR4 antagonist in a xenograft mouse model of inflammatory breast cancer

CXCL12/CXCR4 signaling, being important in the homing of cancer cells to lungs, bone and other organs, is a promising therapeutic target. Our purpose was to determine whether a peptide-based antagonist of CXCR4 would reduce primary tumor growth and/or metastasis in a preclinical mouse model of inflammatory breast cancer. We improved an existing model of inflammatory breast cancer for this study by luciferase transfection of SUM149 cells and the monitoring of such cells in mice by imaging and the luciferase assay. We implanted 2 x 10(6) SUM49-Luc cells along with matrigel into the left thoracic mammary fat pad of nude mice to produce tumors. Our mouse model exhibited important features of inflammatory breast cancer, namely, aggressive local disease, local metastases and distant metastases. To evaluate the efficacy of a CXCR4 antagonist CTCE-9908, by itself or in combination with paclitaxel, we treated groups of ten mice each with CTCE-9908 (25 mg/kg, injected subcutaneously 5 days/week), control peptide SC-9908, paclitaxel (10 mg/kg, injected subcutaneously twice a week), and CTCE-9908 plus paclitaxel concurrently. We assessed all mice weekly by whole-body luciferase imaging to quantify relative primary tumor burden and distant metastases. At the end of the experiment, we quantified primary tumors by weight and lung metastases by luciferase activity assay on tissue lysates. Paclitaxel, a known chemotherapeutic, inhibited primary tumor growth in our model (P < 0.05). CTCE-9908 did not significantly inhibit primary tumor growth or lung metastases as compared to control groups, without or with paclitaxel (P > 0.05). However, CTCE-9908 as a single therapy inhibited organ-specific metastasis to leg (P < 0.05 by chi-squared test and by two-sample t-test).

Histological, Immunohistological, and Ultrastructural Description of Vasculogenic Mimicry in Canine Mammary Cancer

Canine inflammatory mammary cancer (IMC) and human inflammatory breast cancer (IBC) are the most aggressive and lethal type of mammary cancer in female dogs and in women. The generation of microvascular channels by malignant tumor cells (endothelial-like cells [ELCs]) without endothelial cell participation (vasculogenic mimicry) has been reported in human breast cancer, including IBC, and is considered a new type of tumor angiogenesis. The aim of this study was to investigate the presence of ELCs in highly malignant canine mammary tumors (IMC and non-IMC) by histology, inmunohistochemistry (pancytokeratin, cytokeratin 14, vimentin, actin, desmin, vWF, CD31, and CD34), and electron microscopy. This retrospective study included 21 female dogs with diagnoses of IMC and 20 animals with metastatic grade III noninflammatory malignant mammary tumors (MMT). IMC tumors (33.33%) and MMT (5%) showed ELCs forming structures similar to small capillaries. The histological, immunohistochemical (positive to AE1/AE3 and cytokeratin 14, mostly negative to endothelial markers), and ultrastructural characteristics of these cells indicated vasculogenic mimicry. The higher frequency of this phenomenon in inflammatory versus noninflammatory canine mammary cancer is in agreement with previous studies in experimental and spontaneous human IBC, and it could be in relation with the extremely high lymphangiogenic capacity and metastatic lymphangiotropism characteristics of inflammatory breast cancer.

Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study

Inflammatory breast cancer is an aggressive and biologically distinct form with a higher frequency of HER2 overexpression than other breast cancers. For patients with resistance to conventional anthracycline or taxane and trastuzumab treatment, options are limited. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor tyrosine kinases, previously had a 50% response rate in a cohort of 30 patients with HER2-overexpressing (HER2+) recurrent or anthracycline-refractory inflammatory breast cancer. We aimed to assess efficacy of lapatinib in an expanded cohort of patients with relapsed or refractory HER2+ disease. From March, 2005, to September, 2007, 126 patients with relapsed or refractory HER2+ inflammatory breast cancer were treated with lapatinib 1500 mg once daily in a non-randomised, open-label, phase II study. Pretreatment tumour biopsies were done to verify pathological features of inflammatory breast cancer. Skin disease was assessed every 4 weeks, and response in sites of measurable locally advanced or metastatic disease were assessed by response evaluation in solid tumours (RECIST) criteria every 8 weeks. The primary aim was to assess combined objective response rate, by clinically evaluable skin disease criteria and RECIST, if applicable. Analyses were done by intention to treat; patients with missing data were treated as non-responders. This study is registered with ClinicalTrials.gov, number NCT00105950. Clinical presentation and biomarker analysis showed a tumour molecular profile consistent with inflammatory breast cancer. No patients had complete response. 49 patients (39%; 95% CI 30-48) had partial response. Median progression-free survival was 14.6 weeks (95% CI 12.1-16.0), with median duration of response of 20.9 weeks (12.7-32.1). Likelihood of response to lapatinib was not affected by previous treatment with trastuzumab. 130 (92%) of 141 patients had at least one adverse event; 45 (32%) had serious adverse events, the most common were dyspnoea (eight patients) and pleural effusion (six). Five patients had fatal adverse events that were possibly treatment related. Lapatinib monotherapy is a potentially effective treatment for relapsed or refractory HER2+ inflammatory breast cancer. GlaxoSmithKline.

The Epidemiology of Inflammatory Breast Cancer

The epidemiology of inflammatory breast cancer (IBC) has been of great interest to a number of investigators, but epidemiological research has been hampered by the lack of an agreed upon case definition and the relatively small number of patients available to any single investigator or institution. Several features of IBC have become apparent through population-based studies, which, although varying somewhat in case definition, generally agree on some key features of the disease. These include the incidence of the disease, apparently less than 3% of breast cancer cases in the United States, the younger age of onset compared to non-inflammatory breast cancer, the much higher incidence in Black women compared to White, the generally poor outcome of this disease compared to non-inflammatory breast cancer, and the continued increase in reported incidence, particularly as compared with non-inflammatory breast cancer in general and locally advanced breast cancer (LABC) in particular. There is an apparent striking geographic pattern, with a higher percentage of cases reported from North Africa, best documented in Tunisia. The risk factors for developing IBC are suggested by smaller studies with concordant conclusions, and some appear to be different than the risk factors for developing breast cancer in general. For example, obesity appears to be a risk factor for premenopausal IBC but is not for premenopausal non-inflammatory breast cancer. In addition, there is evidence that a young age at first birth predisposes to IBC but is protective against developing non-inflammatory breast cancer. In some malignancies, the use of molecular markers is helpful in defining subgroups that could assist in improving case definition as well as predicting prognosis. The increasing combination of improved epidemiologic and laboratory methods will hopefully accelerate our understanding of this challenging disease.

Molecular epidemiologic features of inflammatory breast cancer: a comparison between Egyptian and US patients

Inflammatory breast cancer (IBC) is a lethal form of breast cancer with unknown etiology. A higher frequency of IBC and a more aggressive IBC phenotype was reported in Egypt than in the United States. This difference in disease frequency and presentation might be related to molecular epidemiologic factors. We used tumor blocks and demographic, epidemiologic, and clinical data of 48 IBC patients from Egypt and 12 patients from the United States. We counted tumor emboli in tumors before and after immunohistochemical staining with lymphatic vessel endothelial receptor-1 (LYVE-1), and measured the expression of RhoC GTPase protein in the two groups. Erythema, edema, and peau d'orange were found in 77% of the Egyptian patients as compared with 29% found in the US patients (P=0.02). The number of tumor emboli was significantly higher in tumors from Egypt (mean+/-SD, 14.1+/-14.0) than in the tumors from the United States (5.0+/-4.0, P=0.01). The number of tumor emboli in LYVE-1 positive vessels was higher in tumors from Egypt (3.5+/-2.8) than tumors from the United States (1.6+/-0.5, P=0.15). We detected a high level of RhoC in 87% of the tumors from Egypt and 14% of the tumors from the United States (P=0.0003). Patients from Egypt have a more aggressive form of IBC than those in the United States. Our analysis of IBC patients shows that distinct molecular phenotypes can be found when these two study populations are compared. Future studies should explore the epidemiologic and environmental exposures and the genetic factors that might lead to the different clinical and molecular features of IBC in patients from these two countries.

Serum Markers and Prognosis in Locally Advanced Breast Cancer

Locally advanced breast cancer (LABC) represents a heterogeneous subgroup of breast cancer with an often dismal outcome. Identifying prognostic factors has acquired great significance for the selection of optimal treatment in individual patients. Between January 1993 and December 1997, 103 patients were treated in our institution with multimodality treatment consisting of neoadjuvant chemotherapy followed by surgery, adjuvant chemotherapy and radiotherapy; tamoxifen was added in hormone receptor-positive cases. In the search for prognostic factors well-established parameters (clinical, pathological and treatment-related) as well as new features with potential value (c-erbB-2, baseline serum levels of CA 15.3 and CEA) were included in the univariate and multivariate analysis. At a median follow-up of 92 months (range, 8-130), the estimated five-year cancer-specific overall survival (OS) and disease-free survival (DFS) were 71.34% and 57.7%, respectively. Among the 22 different variables studied, only 10 were significantly correlated with OS and DFS. In multivariate analysis five retained independent prognostic value for both OS and DFS: tumor grade, serum markers, features of inflammatory breast cancer (IBC), response to neoadjuvant chemotherapy and lymph node status. With cutoff values of 35 U/mL for CA 15.3 and 5 ng/mL for CEA, the probability of five-year OS (Cox hazard ratio 3.91, P = 0.0009) and DFS (Cox hazard ratio 2.40, P = 0.02) decreased from 78% to 52% and from 68% to 47%, respectively, when at least one of these markers was abnormal. Baseline serum levels of CEA and CA 15.3 emerged from this study as strong independent predictors of outcome in LABC, whose value adds to other established prognostic factors such as postoperative nodal status, IBC, histological grade and response to neoadjuvant chemotherapy.

Population-based statistics for women diagnosed with inflammatory breast cancer (United States).

The purpose of this study was to use population-based information to describe the demographic and tumor characteristics of inflammatory breast cancer (IBC) - the most aggressive form of this disease. IBC cases diagnosed during 1994 through 1998 were reported to 26 population-based cancer registries covering approximately 40% of the US population. Rates were expressed per 100,000 female population and age-adjusted to the 2000 US population. Ninety-five percent gamma confidence limits were estimated for the rates. Among the 3626 women diagnosed with IBC during 1994-1998, the majority were 40-59 years old. Most tumors were diagnosed at a regional (68.9%) or distant (25.3%) stage and were poorly differentiated (49.4%). The rate of IBC was 1.3 per 100,000 for all races combined. Black women had the highest risk (1.6) and Asian and Pacific Islander women the lowest (0.7). IBC is an extremely rare form of breast cancer. More precise diagnostic criteria are needed to distinguish it from less aggressive forms of the disease. Future studies should use a population-based design and collect detailed clinical information, including the presence of erythema, edema or peau d'orange appearance of the skin, and other clinical signs of disease.

Inflammatory breast cancer: clinical progress and the main problems that must be addressed.

Inflammatory breast cancer is a rare but highly aggressive form of locally advanced breast cancer. Historically, this disease was uniformly fatal; however, with the advent of induction chemotherapy and carefully coordinated multimodality treatment, the prognosis of these patients has improved. This article reviews the clinical characteristics of inflammatory breast cancer and the recent advances in therapy.

BIOLOGICAL AND CLINICAL RELEVANCE OF PROLIFERATIVE ACTIVITY IN INFLAMMATORY BREAST-CANCER

The hormone receptor status and proliferative activity characteristics of inflammatory breast cancer (IBC) were studied in a series of 46 patients. ER and PgR were measured by the DCC method and proliferative activity was by the H-3-thymidine autoradiographic labeling index (H-3-Tdr-LI). Tumors were ER and PgR positive in 42% and 38% of cases, respectively, whereas median H-3-Tdr-LI was 3.8%. With regard to clinical aspects, overall survival (OS) was not affected by either ER status (36 cases) or H-3-Tdr-LI value (33 cases). On the contrary, PgR(+) status was able to individualize women with a significantly higher probability of OS (X(2) by long rank test, p=0.03) after 35 months of follow-up. In the subgroup of 14 patients subjected to double biopsy performed before and after administration of primary polychemotherapy, the tumor proliferative activity variations were not related to clinical outcome.