Selected 2015 Inflammatory Breast Cancer published research.

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Yaghoobi, R., et al. (2015). Inflammatory Breast Carcinoma Presenting with Two Different Patterns of Cutaneous Metastases: Carcinoma Telangiectaticum and Carcinoma Erysipeloides. The Journal of Clinical and Aesthetic Dermatology, 8(8), 47-51. Free full text is available at link in title.

Cutaneous metastases can have many different clinical presentations. They are seen in patients with advanced malignant disease; however, they can be the initial manifestation of undetected malignancies. Inflammatory breast carcinoma is a rare and aggressive form of breast cancer that has a nonspecific appearance mimicking many benign conditions including mastitis, breast abscesses, and/or dermatitis. The authors report the case of a 40-year-old woman with inflammatory breast carcinoma presenting with violaceous papulovesicular lesions resembling lymphangioma circumscriptum and erythematous patches resembling erysipelas. These lesions represent two different types of cutaneous metastases, both of which were the initial signs of inflammatory breast carcinoma in the patient described herein. Skin biopsy of lesions confirmed invasive breast cancer and further prompted a work up for inflammatory breast carcinoma. This case demonstrates the importance of follow-up for all breast lesions, even those considered to be of benign nature, for they can be presenting signs of metastatic breast cancer.

Hall, C. S., et al. (2015). Circulating Tumor Cells and Recurrence After Primary Systemic Therapy in Stage III Inflammatory Breast Cancer. Journal of the National Cancer Institute, 107(11). Abstract below, free full text is not available.

Inflammatory breast cancer (IBC) is rare and aggressive, with poor survival. While circulating tumor cells (CTCs) predict outcome in non-IBC patients, little data exists regarding their prognostic significance in IBC. This prospective study analyzed blood samples for CTCs from 63 stage III IBC patients to determine if CTCs present after primary systemic chemotherapy predicted relapse. CTC identification was not associated with tumor characteristics, lymph node positivity, or complete pathologic response to systemic therapy. At mean follow-up of 38 months, multivariable analysis demonstrated that detection of one or more CTCs predicted shortened relapse-free (log-rank P = 0.005, hazard ratio [HR] = 4.22, 95% confidence interval [CI] = 1.67 to 10.67, Cox P = 0.002) but not overall survival (log-rank P = 0.54, HR = 1.53, 95% CI = 0.41 to 5.79, Cox P = 0.53). All statistical tests were two-sided. In this study, CTCs after primary chemotherapy identified IBC patients at high risk for relapse.

Loewen, A. H., et al. (2015). Case report: hormone receptor positive, HER2/neu negative inflammatory breast cancer in a male patient. South Dakota Medicine, 68(10), 435-40. Abstract below, free full text is not available.

Inflammatory breast cancer is a rare and aggressive disease found almost exclusively in women. We present a case of a 51-year-old male with inflammatory breast carcinoma. The patient presented with a mass measuring roughly 7 cm with overlying erythema, peau d’orange appearance, and prominent nipple retraction. Core biopsy analysis demonstrated estrogen and progesterone receptor positive, HER2/neu receptor negative invasive ductal carcinoma. A PET scan revealed contralateral supraclavicular lymph node metastasis. The patient refused chemotherapy and radiation and was not a surgical candidate. Ultimately he opted for therapy with strictly an aromatase inhibitor. Most recent follow-up at 12 months demonstrated improvement of metastatic lesions on PET scan. Local progression of disease was noted on physical exam and the patient decided to add everolimus and radiation therapy while continuing an aromatase inhibitor. Retrospective studies have demonstrated increased survival of inflammatory breast cancer diagnosed in women with the utilization of neoadjuvant chemotherapy, surgical excision, and radiation therapy. Unfortunately, due to the rarity of the disease, no specific optimal treatment guidelines have been established for men diagnosed with this disease.

Mejri, N., et al. (2015). Inflammatory breast cancer in Tunisia from 2005 to 2010: Epidemiologic and anatomoclinical transitions from published data. Asian Pacific Journal of Cancer Prevention, 16(3), 1277-80. Free full text is available at link in title.

To report epidemiologic and anatomoclinical transitions of inflammatory breast cancer (IBC) in Tunisia.
Data including clinico-pathological data for 208 cases of T4d or PEV 3 non-metastatic breast cancer diagnosed between 2005 and 2010 were collected from patient records. Chi2 and Z tests were used to compare variables with two Tunisian historical series and a series about Arab-American patients.
Thirty three percent of our patients had their first child before 23 years of age and 56% had their menarche before 12 years, 75% never receiving oral contraception. Obesity was observed in 42% of women and IBC occurred during pregnancy in 13% of cases. Tumor grade was II-III in 90% of cases, HR was negative in 52%, HER2 was over expressed in 31% and invasion of more than 3 axillary nodes occurred in 18% of patients. We observed a pCR rate of 19% after neoadjuvant treatment (anthracyline-taxane used in 79%, trastuzumab in 27% ). Compared to historical Tunisian series (since 1996), IBC epidemiology remained stable in terms of median age, menopausal status and obesity. However we observed a significant decrease in median clinical tumor size and number of positive axillary lymph nodes. Comparison to IBC in Arab-Americans showed a significant difference in terms of median age, menopausal status, positivity of hormonal receptors and educational level.
Our assessment of epidemiologic transition showed a reduction of clinco-pathological stage of IBC, keeping the same characteristics as compared to Tunisian historical series over a period of 14 years. Features seem to be different in Arab-American patients, probably related to migration, “occidentalization” of life style and improvement in socio-economic level.

Putcha, P., et al. (2015). HDAC6 activity is a non-oncogene addiction hub for inflammatory breast cancers. Breast Cancer Research, 17(1). doi:10.1186/s13058-015-0658-0. Free full text is available at link in title.

Inflammatory breast cancer (IBC) is the most lethal form of breast cancers with a 5-year survival rate of only 40 %. Despite its lethality, IBC remains poorly understood which has greatly limited its therapeutic management. We thus decided to utilize an integrative functional genomic strategy to identify the Achilles’ heel of IBC cells.
We have pioneered the development of genetic tools as well as experimental and analytical strategies to perform RNAi-based loss-of-function studies at a genome-wide level. Importantly, we and others have demonstrated that these functional screens are able to identify essential functions linked to certain cancer phenotypes. Thus, we decided to use this approach to identify IBC specific sensitivities.
We identified and validated HDAC6 as a functionally necessary gene to maintain IBC cell viability, while being non-essential for other breast cancer subtypes. Importantly, small molecule inhibitors for HDAC6 already exist and are in clinical trials for other tumor types. We thus demonstrated that Ricolinostat (ACY1215), a leading HDAC6 inhibitor, efficiently controls IBC cell proliferation both in vitro and in vivo. Critically, functional HDAC6 dependency is not associated with genomic alterations at its locus and thus represents a non-oncogene addiction. Despite HDAC6 not being overexpressed, we found that its activity is significantly higher in IBC compared to non-IBC cells, suggesting a possible rationale supporting the observed dependency.
Our finding that IBC cells are sensitive to HDAC6 inhibition provides a foundation to rapidly develop novel, efficient, and well-tolerated targeted therapy strategies for IBC patients.

Ross, J., et al. (2015). Comprehensive genomic profiling of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations. Breast Cancer Research and Treatment, 154(1), 155-62. doi:10.1007/s10549-015-3592-z. Abstract below, free full text is not available.

Inflammatory breast cancer (IBC) is a distinct clinicopathologic entity that carries a worse prognosis relative to non-IBC breast cancer even when matched for standard biomarkers (ER/PR/HER2). The objective of this study was to identify opportunities for benefit from targeted therapy, which are not currently identifiable in the standard workup for advanced breast cancer. Comprehensive genomic profiling on 53 IBC formalin-fixed paraffin-embedded specimens (mean, 800× + coverage) using the hybrid capture-based FoundationOne assay. Academic and community oncology clinics. From a series of 2208 clinical cases of advanced/refractory invasive breast cancers, 53 cases with IBC were identified. The presence of clinically relevant genomic alterations (CRGA) in IBC and responses to targeted therapies. CRGA were defined as genomic alterations (GA) associated with on label targeted therapies and targeted therapies in mechanism-driven clinical trials. For the 44 IBCs with available biomarker data, 19 (39 %) were ER-/PR-/HER2- (triple-negative breast cancer, TNBC). For patients in which the clinical HER2 status was known, 11 (25 %) were HER2+ with complete (100 %) concordance with ERBB2 (HER2) amplification detected by the CGP assay. The 53 sequenced IBC cases harbored a total of 266 GA with an average of 5.0 GA/tumor (range 1-15). At least one alteration associated with an FDA approved therapy or clinical trial was identified in 51/53 (96 %) of cases with an average of 2.6 CRGA/case. The most frequently altered genes were TP53 (62 %), MYC (32 %), PIK3CA (28 %), ERBB2 (26 %), FGFR1 (17 %), BRCA2 (15 %), and PTEN (15 %). In the TNBC subset of IBC, 8/19 (42 %) showed MYC amplification (median copy number 8X, range 7-20) as compared to 9/32 (28 %) in non-TNBC IBC (median copy number 7X, range 6-21). Comprehensive genomic profiling uncovered a high frequency of GA in IBC with 96 % of cases harboring at least 1 CRGA. The clinical benefit of selected targeted therapies in individual IBC cases suggests that a further study of CGP in IBC is warranted.

Champion, L., et al. (2015). 18F-FDG PET/CT to predict response to neoadjuvant chemotherapy and prognosis in inflammatory breast cancer. Journal of Nuclear Medicine, 56(9), 1315-21. doi:10.2967/jnumed.115.158287. Abstract below, free full text is not available.

The aim of this prospective study was to assess the predictive value of 18F-FDG PET/CT imaging for pathologic response to neoadjuvant chemotherapy (NACT) and outcome in Inflammatory Breast Cancer (IBC) patients.
Twenty-three consecutive patients (51 years±12.7) with newly diagnosed IBC, assessed by PET/CT scan at baseline (PET1), after the third course of NACT (PET2) and before surgery (PET3), were included. Patients were divided into 2 groups according to the pathologic response assessed by the Sataloff classification: pCR for complete responders (TA and NA or NB) and non-pCR for non-complete responders (not stage A for tumor and/or not NA or NB for lymph nodes). In addition to SUVmax measurements, a global breast Metabolic Tumor Volume (MTV) was delineated using a semi-automatic segmentation method. Changes of SUVmax and MTV between PET1 and PET2 (ΔSUV1-2; ΔMTV1-2) and PET1 and PET3 (ΔSUV1-3; ΔMTV1-3) were measured.
Mean SUVmax on PET1, PET2 and PET3 were not statistically different between the 2 pathologic response groups. Using ROC analysis, a 72% cutoff of ΔSUV1-3 provided the best performance to predict residual disease with sensitivity, specificity and accuracy of 61%, 80%, and 65%, respectively. On univariate analysis, the 72% cutoff of ΔSUV1-3 was the best predictor of Distant Metastasis-Free Survival (P = 0.05). On multivariate analysis, the 72% cutoff ΔSUV1-3 was an independent predictor of DMFS (P = 0.01).
Our results emphasize the good predictive value of ΔSUVmax between baseline and before surgery to assess pathologic response and survival in IBC patients undergoing NACT.

Warren, L.E., et al. (2015). Inflammatory breast cancer: patterns of failure and the case for aggressive locoregional management. Annals of Surgical Oncology, 22(8), 2483-91. doi:10.1245/s10434-015-4469-4. Abstract below, free full text is not available.

Inflammatory breast cancer (IBC) is a rare and aggressive subtype. This study analyzes the patterns of failure in patients with IBC treated at our institution.
We retrospectively analyzed the records of 227 women with IBC presenting between 1997 and 2011. Survival analysis was used to calculate overall survival (OS) and disease-free survival. Competing risk analysis was used to calculate locoregional recurrence (LRR).
A total of 173 patients had locoregional-only disease at presentation (non-MET). Median follow-up in the surviving patients was 3.3 years. Overall, 132 (76.3 %) patients received trimodality therapy with chemotherapy, surgery, and radiotherapy. Three-year OS was 73.1 % [95 % confidence interval (CI) 64.9-82.4]. Cumulative LRR was 10.1, 16.9, and 21.3 % at 1, 2, and 3 years, respectively. No variable was significantly associated with LRR. Fifty-four patients had metastatic disease at presentation (MET). Median follow-up in the surviving patients was 2.6 years. Three-year OS was 44.3 % (95 % CI 31.4-62.5). Twenty-four (44.4 %) patients received non-palliative local therapy (radiotherapy and/or surgery). For these patients, median OS after local therapy was 2 years. Excluding six patients who received local therapy for symptom palliation, the crude incidence of locoregional progression or recurrence (LRPR) was 17 % (4/24) for those who received local therapy compared with 57 % (13/23) for those who did not.
For non-MET patients, LRR remains a problem despite trimodality therapy. More aggressive treatment is warranted. For MET patients, nearly 60 % have LRPR with systemic therapy alone. Local therapy should be considered in the setting of metastatic disease to prevent potential morbidity of progressive local disease.

Budach, W., et al. (2015). DEGRO practical guidelines for radiotherapy of breast cancer V: therapy for locally advanced and inflammatory breast cancer, as well as local therapy in cases with synchronous distant metastases. Strahlentherapie Und Onkologie, 191(8), 623-33. doi:10.1007/s00066-015-0843-1. Free full text available in English may be found at link in title.

The purpose of this work is to give practical guidelines for radiotherapy of locally advanced, inflammatory and metastatic breast cancer at first presentation.
A comprehensive survey of the literature using the search phrases “locally advanced breast cancer”, “inflammatory breast cancer”, “breast cancer and synchronous metastases”, “de novo stage IV and breast cancer”, and “metastatic breast cancer” and “at first presentation” restricted to “clinical trials”, “randomized trials”, “meta-analysis”, “systematic review”, and “guideline” was performed and supplemented by using references of the respective publications.
Based on the German interdisciplinary S3 guidelines, updated in 2012, this publication addresses indications, sequence to other therapies, target volumes, dose, and fractionation of radiotherapy.
International and national guidelines are in agreement that locally advanced, at least if regarded primarily unresectable and inflammatory breast cancer should receive neoadjuvant systemic therapy first, followed by surgery and radiotherapy. If surgery is not amenable after systemic therapy, radiotherapy is the treatment of choice followed by surgery, if possible. Surgery and radiotherapy should be administered independent of response to neoadjuvant systemic treatment. In patients with a de novo diagnosis of breast cancer with synchronous distant metastases, surgery and radiotherapy result in considerably better locoregional tumor control. An improvement in survival has not been consistently proven, but may exist in subgroups of patients.
Radiotherapy is an important part in the treatment of locally advanced and inflammatory breast cancer that should be given to all patients regardless to the intensity and effect of neoadjuvant systemic treatment and the extent of surgery. Locoregional radiotherapy in patients with primarily distant metastatic disease should be prescribed on an individual basis.

Cohen, E.N., et al. (2015). Inflammation mediated metastasis: immune induced epithelial-to-mesenchymal transition in inflammatory breast cancer cells. PLoS One, 10(7). doi:10.1371/journal.pone.0132710. Free full text is available at link in article title.

Inflammatory breast cancer (IBC) is the most insidious form of locally advanced breast cancer; about a third of patients have distant metastasis at initial staging. Emerging evidence suggests that host factors in the tumor microenvironment may interact with underlying IBC cells to make them aggressive. It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT) in these cells. We hypothesized that soluble factors secreted by activated immune cells can induce an EMT in IBC and thus promote metastasis. In a pilot study of 16 breast cancer patients, TNF-α production by peripheral blood T cells was correlated with the detection of circulating tumor cells expressing EMT markers. In a variety of IBC model cell lines, soluble factors from activated T cells induced expression of EMT-related genes, including FN1, VIM, TGM2, ZEB1. Interestingly, although IBC cells exhibited increased invasion and migration following exposure to immune factors, the expression of E-cadherin (CDH1), a cell adhesion molecule, increased uniquely in IBC cell lines but not in non-IBC cell lines. A combination of TNF-α, IL-6, and TGF-β was able to recapitulate EMT induction in IBC, and conditioned media preloaded with neutralizing antibodies against these factors exhibited decreased EMT. These data suggest that release of cytokines by activated immune cells may contribute to the aggressiveness of IBC and highlight these factors as potential target mediators of immune-IBC interaction.

Rea, D., et al. (2015). Inflammatory breast cancer: time to standardise diagnosis assessment and management, and for the joining of forces to facilitate effective research. British Journal of Cancer, 112(9), 1613-5. doi: 10.1038/bjc.2015.115. Free full text is available at link in article title.

Fouad, T., et al. (2015). Overall survival differences between patients with inflammatory and noninflammatory breast cancer presenting with distant metastasis at diagnosis. Breast Cancer Research and Treatment, 152(2), 407-16. doi: 10.1007/s10549-015-3436-x. Abstract below, free full text is not available.

Inflammatory breast cancer (IBC) is a rare and aggressive disease. Previous studies have shown that among patients with stage III breast cancer, IBC is associated with a worse prognosis than noninflammatory breast cancer (non-IBC). Whether this difference holds true among patients with stage IV breast cancer has not been studied. We tested the hypothesis that overall survival (OS) is worse in patients with IBC than in those with non-IBC among patients with distant metastasis at diagnosis (stage IV disease). We reviewed the records of 1504 consecutive patients with stage IV breast cancer (IBC: 206; non-IBC: 1298) treated at our institution from 1987 through 2012. Survival curves for IBC and non-IBC subcohorts were compared. The Cox proportional hazards model was used to determine predictors of OS. The median follow-up period was 4.7 years. IBC was associated with shorter median OS time than non-IBC (2.27 vs. 3.40 years; P = 0.0128, log-rank test). In a multicovariate Cox model that included 1389 patients, the diagnosis of IBC was a significant independent predictor of worse OS (hazard ratio = 1.431, P = 0.0011). Other significant predictors of worse OS included Black (vs. White) ethnicity, younger age at diagnosis, negative HER2 status, and visceral (vs. nonvisceral) site of metastasis. IBC is associated with shorter OS than non-IBC in patients with distant metastasis at diagnosis. The prognostic impact of IBC should be taken into consideration among patients with stage IV breast cancer.

Wecsler, J., et al. (2015). Lymph node status in inflammatory breast cancer. Breast Cancer Research and Treatment, 151(1), 113-20. doi: 10.1007/s10549-015-3367-6. Abstract below, free full text is not available.

Positive lymph node status in breast cancer is known to be an adverse prognostic factor, but the effect of lymph node (LN) status in inflammatory breast cancer (IBC) has not been evaluated. This study was designed to investigate the association between lymph node status and overall survival (OS) in individuals with IBC. Using the Surveillance, Epidemiology, and End Results (SEER) 18 registry, we collected data on 761 patients diagnosed with non-metastatic IBC from 2004 to 2008. Survival analysis was performed using the Kaplan-Meier method. Cox proportional hazard regression was performed to evaluate univariate and multivariate associations between estrogen and progesterone receptor (ER/PR) status, treatment, and OS. Positive nodal status was associated with a significant decrease in OS (p < 0.001). Five-year survival for LN-positive and LN-negative patients was 49 and 66 %, respectively. In node-positive patients, ER or PR positivity was associated with improved OS, (p = 0.025, p = 0.007). In node-positive patients, the combination of surgery and radiation therapy improved OS when compared with surgery alone (p = 0.002). Nearly 80 % of the patients in this study had nodal metastasis. Positive nodal status was found to be an adverse prognostic factor. ER/PR positivity and treatment with surgery and radiation in node-positive patients was found to improve outcomes. Further studies are required to characterize the biology of IBC and guide the optimal treatment of this disease.

Gonçalves, A., et al. (2015). Unicancer-pegase 07 study: a randomized phase 3 trial evaluating post-operative docetaxel-5fu regimen after neo-adjuvant dose- intense chemotherapy for treatment of inflammatory breast cancer. Annals of Oncology: the official scientific journal of ESMO, 26(8), 1692-7. doi: 10.1093/annonc/mdv216. Abstract below, free full text is not available.

Inflammatory breast cancer (IBC) is a rare and aggressive disease requiring a multimodal treatment. We evaluated the benefit of adding docetaxel-5-fluorouracil (D-5FU) regimen after preoperative dose-intense (DI) epirubicin-cyclophosphamide (EC) and locoregional treatment in IBC patients.
PEGASE 07 was a national randomized phase III open-label study involving 14 hospitals in France. Women with nonmetastatic IBC were eligible and randomly assigned to receive either four cycles of DI EC (E 150 mg/m(2) and C 4000 mg/m(2) every 3 weeks with repeated hematopoietic stem cell support), then mastectomy with axillary lymph node dissection, and radiotherapy (arm A) or the same treatment followed by four cycles of D-5FU (D 85 mg/m(2), day 1 and 5FU 750 mg/m(2)/day continuous infusion, days 1-5 every 3
weeks) administered postradiotherapy (arm B). Patients with hormone receptor-positive tumors received hormonal therapy. Disease- free survival (DFS) was the primary end point. Secondary end points included tolerance, pathological complete response (pCR) rate, and overall survival (OS).
Between January 2001 and May 2005, 174 patients were enrolled and treated (87 in each arm). Median follow-up was similar in both arms: 59.6 months [95% confidence interval (CI) 58.4-60.3] in arm A and 60.5 months (95% CI 58.3-61.4) in arm B. The estimated 5-year DFS rates were not different: 55% (95% CI 43.9-64.7) in arm A and 55.5% (95% CI 44.3-65.3) in arm B [hazard ratio (HR) = 0.94 (0.61- 1.48); P = 0.81]. Identical results were observed for 5-year OS: 70.2% (95% CI 59.1-78.8) in arm A and 70% (95% CI 58.8-78.7) in arm B [HR = 0.93 (0.55-1.60); P = 0.814]. Following DI EC induction, in-breast and global (breast plus nodes) pCR were 28.9% and 20.1%, respectively. Estrogen receptor and pCR status were independently associated with survival.
The addition of D-5FU after preoperative DI EC and standard local therapy did not improve DFS in IBC.

Siamakpour-Reihani, S., et al. (2015). Genomic profiling in locally advanced and inflammatory breast cancer and its link to DCE-MRI and overall survival. International Journal of Hyperthermia, 31(4), 386-95. doi: 10.3109/02656736.2015. Abstract below, free full text is not available.

We have previously reported that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion patterns obtained from locally advanced breast cancer (LABC) patients prior to neoadjuvant therapy predicted pathologic clinical response. Genomic analyses were also independently conducted on the same patient population. This retrospective study was performed to test two hypotheses: (1) gene expression profiles are associated with DCE-MRI perfusion patterns, and (2) association between long-term overall survival data and gene expression profiles can lead to the identification of novel predictive biomarkers.
We utilised RNA microarray and DCE-MRI data from 47 LABC patients, including 13 inflammatory breast cancer (IBC) patients. Association between gene expression profile and DCE-MRI perfusion patterns (centrifugal and centripetal) was determined by Wilcoxon rank sum test. Association between gene expression level and survival was assessed using a Cox rank score test. Additional genomic analysis of the IBC subset was conducted, with a period of follow-up of up to 11 years. Associations between gene expression and overall survival were further assessed in The Cancer Genome Atlas Data Portal.
Differences in gene expression profiles were seen between centrifugal and centripetal perfusion patterns in the sulphotransferase family, cytosolic, 1 A, phenol-preferring, members 1 and 2 (SULT1A1, SULT1A2), poly (ADP-ribose) polymerase, member 6 (PARP6), and metastasis tumour antigen1 (MTA1). In the IBC subset our analyses demonstrated that differential expression of 45 genes was associated
with long-term survival.
Here we have demonstrated an association between DCE-MRI perfusion patterns and gene expression profiles. In addition we have reported on candidate prognostic biomarkers in IBC patients, with some of the genes being significantly associated with survival in IBC and LABC.

Bertucci, F., et al. (2015). PDL1 expression in inflammatory breast cancer is frequent and predicts for the pathological response to chemotherapy. Oncotarget, 6(15), 13506-19. Free full text is available at link in article title.

We retrospectively analyzed PDL1 mRNA expression in 306 breast cancer samples, including 112 samples of an aggressive form, inflammatory breast cancer (IBC). PDL1 expression was heterogeneous, but was higher in IBC than in non-IBC. Compared to normal breast samples, PDL1 was overexpressed in 38% of IBC. In IBC, PDL1 overexpression was associated with estrogen receptor-negative status, basal and ERBB2-enriched aggressive subtypes, and clinico-biological signs of anti-tumor T-cell cytotoxic response. PDL1 overexpression was associated with better pathological response to chemotherapy, independently of histo-clinical variables and predictive gene expression signatures. No correlation was found with metastasis-free and overall specific survivals. In conclusion, PDL1 overexpression in IBC correlated with better response to chemotherapy. This seemingly counterintuitive correlation between expression of an immunosuppressive molecule and improved therapeutic response may be resolved if PDL1 expression is viewed as a surrogate marker of a strong antitumor immune response among patients treated with immunogenic chemotherapy. In such patients, PDL1 inhibition could protect activated T-cells or reactivate inhibited T-cells and improve the therapeutic response, notably when associated with immunogenic chemotherapy.

Dawood, S., & Cristofanilli, M. (2015). IBC as a rapidly spreading systemic disease: Clinical and targeted approaches using the neoadjuvant model. Journal of the National Cancer Institute. Monographs. (15), 56-9. doi: 10.1093/jncimonographs/lgv017 Abstract below, free full text is not available.

Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2.5% of all breast cancer cases. It is characterized by rapid progression, younger age of onset as compared with other cancers, local and distant metastases, and lower overall survival. The multidisciplinary management of IBC includes neoadjuvant systemic chemotherapy, surgery, radiotherapy, and hormonal therapy in hormone receptor-positive disease. Pathological complete response represents an important prognostic factor suggesting IBC as the ideal in-vivo model for therapeutic development. Molecular subtyping demonstrated higher frequency of basal-like an HER2 disease in IBC compared with non-IBC indicating the areas of novel therapeutic interventions. The prospective testing of HER2-targeted therapies (eg, trastuzumab and lapatinib) demonstrated the validity of this concept and the potential to change the outcome of this aggressive disease.

Warren, L., et al. (2015). Inflammatory breast cancer and development of brain metastases: risk factors and outcomes. Breast Cancer Research and Treatment, 151(1), 225-32. doi: 10.1007/s10549-015-3381-8. Abstract below, free full text not available.

Brain metastases are associated with significant morbidity. Minimal research has been conducted on the risk factors for and incidence of brain metastases in women with inflammatory breast cancer (IBC). 210 women with Stage III or IV IBC diagnosed from 1997-2011 were identified. Competing risk analysis and competing risks regression were used to calculate the incidence of brain metastases and identify significant risk factors. After a median follow-up in surviving patients of 2.8 years (range 0.6-7.6) and 3.3 years (range 0.2-14.5) in the 47 and 163 patients with (MET) and without (non-MET) metastatic disease at diagnosis, 17 (36 %) and 30 (18 %) developed brain metastases, respectively. The cumulative incidence at 1, 2, and 3 years was 17 % [95 % confidence interval (CI), 8-30], 34 % (95 % CI, 20-48), and 37 % (95 % CI, 22-51) for the MET cohort. The corresponding non-MET values were 4 % (95 % CI, 2-8), 8 % (95 % CI 5-13), and 15 % (95 % CI, 10-22). Once non-MET patients developed extracranial distant metastases, the subsequent 1, 2, and 3 years cumulative incidence of brain metastases was 18 % (95 % CI, 10-28), 25 % (95 % CI, 15-36), and 31 % (95 % CI, 20-43). On multivariate analysis, brain metastases were associated with younger age [hazard ratio (HR), 0.73; 95 % CI, 0.53-1.00; P = 0.05] and distant metastases at diagnosis (HR, 2.33; 95 % CI, 1.11-4.89; P = 0.03). The incidence of brain metastases is high in women with IBC. Particularly for patients with extracranial distant metastases, routine screening with magnetic resonance imaging should be considered.

Chang, EI, et al. (2015). Challenging a traditional paradigm: 12-year experience with autologous free flap breast reconstruction for inflammatory breast cancer. Plastic and Reconstructive Surgery, 135(2), 262e-9e. Abstract below, free full text not available.

Inflammatory breast cancer is a rare but aggressive breast cancer with an overall poor prognosis. Traditionally, reconstruction has not been offered, because of poor long-term survival, the need for multimodality treatment, and complex treatment sequencing. The authors examined the safety and feasibility of free flap breast reconstruction for inflammatory breast cancer.
A retrospective analysis of all patients who underwent reconstruction for inflammatory breast cancer from January of 2000 to December of 2012 was conducted.
Of 830 inflammatory breast cancer patients, 59 (7.1 percent; median age, 48 years; range, 27 to 65 years) underwent free flap reconstruction. All patients received chemotherapy and radiation therapy. Most patients (n = 52) underwent delayed reconstruction. Five patients with a history of prior partial mastectomy and irradiation developed inflammatory breast cancer and underwent immediate reconstruction following completion mastectomy. Two others underwent immediate chest wall and breast reconstruction following resection. Thirteen patients underwent bilateral reconstruction, and seven required a bipedicled abdominal flap for the unilateral mastectomy defect. Thirty-seven patients (62.7 percent) required revision of the reconstructed breast, and 29 (49.2 percent) had a contralateral balancing procedure to optimize symmetry. Complications occurred in 21 patients (35.6 percent), with one total flap loss (1.7 percent). The median length of follow-up was 43.9 months; 49 patients (83.1 percent) were alive without evidence of recurrent disease.
Autologous free flap breast reconstruction can be performed safely in inflammatory breast cancer patients, with acceptable complication rates and without an increased risk for flap loss. Inflammatory breast cancer should not preclude free flap breast reconstruction.

Zhang, W., & Zhang, J. (2015). miR-181c promotes proliferation via suppressing PTEN expression in inflammatory breast cancer. International Journal of Oncology, 46(5), 2011-20. doi: 10.3892/ijo.2015.2896. Abstract below, free full text is not available.

Primary inflammatory breast cancer (IBC) accounts for ~6% of new breast cancer cases. Even with multimodality treatment, the 5-year disease-free survival is <45%, thus making IBC the most deadly form of locally advanced breast cancer. Better understanding of the pathogenesis of IBC is essential to the design of effective therapy. We found that miR-181c was upregulated in IBC, implying that it could be a useful prognostic marker for IBC and a novel therapeutic target for the intervention of disease. Elucidating why the gene is overexpressed and how to downregulate it will help us to further understand the pathogenesis and progression of the disease and offer new targets for therapies. In this study, we showed that miR-181c as an oncogene promoted proliferation and it inhibited PTEN protein expression by targeting 3′-UTR of PTEN mRNA in IBC SUM149 cells. Moreover, PTEN was not only downregulated in IBC, but also inhibited proliferation in SUM149 cells and introduction of PTEN cDNA lacking the predicted sites of 3′-UTR abrogated miR-181c cellular function, suggesting that miR-181c inhibited proliferation by downregulating PTEN expression in IBC. Thus, targeting miR-181c and restoration of PTEN can be used in conjunction with other therapies to prevent progression of IBC.

Downey, C., et al. (2015). Prognostic significance of tumour stroma ratio in inflammatory breast cancer. Springerplus, doi: 10.1186/s40064-015-0852-7. Free full text is available at link in article title.

Tumour stroma ratio (TSR) is emerging as an important prognostic indicator in cancer. We have previously shown TSR to be prognostic in oestrogen receptor positive breast cancer. Its role in inflammatory breast cancer, a rare but aggressive form of breast cancer, has not been identified. Here we aimed to determine the prognostic significance of TSR in a cohort of patients with inflammatory breast carcinoma. TSR was measured by point counting virtual H&E stained tissue sections in 45 inflammatory breast cancer cases. The whole tumour area was sampled. Optimum cut-offs to distinguish high and low TSR was determined by log-rank test. The relationship of TSR to overall survival and disease-free survival (DFS) was analysed alongside multivariate analysis. The optimal cut-offs between high and low TSR were determined to be 31% for OS and 46% for DFS. There was no significant difference in OS (p = 0.53) nor DFS (p = 0.66) between high and low TSR groups. Multivariate analysis did not demonstrate any new trends, within the limits of a small data sample. A significant correlation was found between pathological response to neoadjuvant chemotherapy and survival (p = 0.008). There is no evidence that TSR has prognostic significance in inflammatory breast cancer. When compared with published data in non-inflammatory breast carcinoma, this supports the view that differences in stromal biology exist between tumour types and highlights the importance of considering this when interpreting the prognostic value of TSR. However, these findings must be interpreted in the light of the small sample size.

Kogawa, T., et al (2015). Association of body mass index changes during neoadjuvant chemotherapy with pathologic complete response and clinical outcomes in patients with locally advanced breast cancer. Journal of Cancer, 6(4), 310-18. Free full text is available at link in article title.

The purpose of this study was to determine the association between body mass index (BMI) measurements (baseline BMI and changes in BMI during neoadjuvant systemic treatment [NST]) and clinical efficacy (pathologic complete response [pCR] rate and survival outcomes) in locally advanced breast cancer (LABC). We hypothesized that high baseline BMI and increases in BMI during NST are associated with lower pCR rates and poorer clinical outcomes in LABC. We retrospectively reviewed the medical records of 1002 patients, 204 with primary inflammatory breast cancer (IBC) and 798 with stage III non-IBC, who underwent standard NST and definitive surgery between November 1, 2006, and December 31, 2012. The median follow-up time for the survivors was 19.6 months (0.4 – 67.8 months). The pCR rates of patients whose BMI increased or decreased were 23.2% and 18.1%, respectively, (p=0.048). The unadjusted overall survival (OS) was significantly better in the group with increased BMI (p=0.006). However, increased BMI was not an independent predictor of pCR and clinical outcomes (recurrence-free survival and OS) after adjusting for other clinical variables. In subset analyses, increased BMI as a continuous variable was an independent predictor of higher pCR rates in the normal BMI/underweight group (odds ratio [OR]=1.35, 95% confidence interval [CI]: 1.06- 0.71, p=0.015). Increased BMI (BMI change ≥0 vs. <0) was also an independent predictor of pCR (OR=1.65, 95% CI: 1.00-2.72, p=0.049) in the postmenopausal group. Our results show that increasing BMI shows improved clinical outcome in terms of better pCR rates in normal BMI/underweight group and in the postmenopausal group. These results contradict previously reported findings on the association between high BMI and poor clinical efficacy regarding pCR rate and survival outcomes in early-stage breast cancer. Thus, the role of BMI in breast cancer may depend on patients’ clinical characteristics such as advanced stage.

Pierga, J., et al. (2015). Pathological response and circulating tumor cell count identifies treated HER2 inflammatory breast cancer patients with excellent prognosis: BEVERLY-2 survival data. Clinical Cancer Research, 21(6), 1298-304. doi: 10.1158/1078-0432.CCR-14-1705. Abstract below, free full text not available.

Purpose: The BEVERLY-2 single-arm phase 2 trial assessed the efficacy and safety of combining neoadjuvant chemotherapy with bevacizumab and trastuzumab for the treatment of HER2-positive inflammatory breast cancer (IBC). Here we report the results of a pre-planned survival analysis at three years of follow-up, along with the association between outcome and circulating biomarkers and pathological complete response (pCR). Experimental design: Patients received fluorouracil, epirubicin, cyclophosphamide and bevacizumab (cycles 1-4) and docetaxel, trastuzumab and bevacizumab (cycles 5-8) prior to surgery, followed by trastuzumab and bevacizumab for 30 weeks post-surgery. Circulating tumor (CTC) and endothelial cell (CEC) counts were assessed at baseline, cycle 5, pre-operative, post-operative and at one year. Results: 52 patients were included. The 3-year disease-free survival (DFS) rate was 68% and overall survival (OS) rate was 90%. pCR (centrally reviewed) was strongly associated with 3-year DFS (80% and 53% in patients with/without pCR, respectively [p=0.03]). CTC detection also independently predicted 3-year DFS (81% vs. 43% for patients with <1 vs. ≥1 CTC/7.5 mL at baseline [p=0.01]). Patients with no CTC detected at baseline and with pCR had a high 3-year DFS (95%). CEC changes during treatment had no prognostic value.

Conclusions: Our study suggests that the prognosis of IBC relies on more than the achievement of pCR and highlights the role of early hematogenous tumor dissemination as assessed by CTCs. Combining these two prognostic factors isolates a subgroup of IBC with excellent survival when treated with bevacizumab and trastuzumab-containing regimens.

Mego, M., et al. (2015). Circulating tumor cells in newly diagnosed inflammatory breast cancer. Breast Cancer Research: BCR, 17(1), doi: 10.1186/s13058-014-0507-6. Free full text is available at link in article title.

Circulating tumor cells (CTCs) are an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer. Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. The prognostic value of a CTC count in newly diagnosed IBC has not been established. The aim of this study was to assess the prognostic value of a baseline CTC count in patients with newly diagnosed IBC.
This retrospective study included 147 patients with newly diagnosed IBC (77 with locally advanced and 70 with metastatic IBC) treated with neoadjuvant therapy or first-line chemotherapy during the period from January 2004 through December 2012 at The University of Texas MD Anderson Cancer Center. CTCs were detected and enumerated by using the CellSearch system before patients were started with chemotherapy.
The proportion of patients with ≥1 CTC was lower among patients with stage III than among patients with metastatic IBC (54.5% versus 84.3%; P = 0.0002); the proportion of patients with ≥5 CTCs was also lower for stage III than for metastatic IBC (19.5% versus 47.1%; P = 0.0004). Patients with fewer than five CTCs had significantly better progression-free survival (PFS) (hazard ratio (HR) = 0.60; P = 0.02) and overall survival (HR = 0.59; P = 0.03) than patients with five or more CTCs. Among patients with stage III IBC, there was a nonsignificant difference in PFS (HR = 0.66; 95% confidence interval (CI), 0.31 to 1.39; P = 0.29) and OS (HR = 0.54; 95% CI, 0.24 to 1.26; P = 0.48) in patients with no CTCs compared with patients with one or more CTCs. In multivariate analysis, CTC was prognostic for PFS and OS independent of clinical stage.

Kai, M., et al. (2015). Clinical characteristics and outcome of bone-only metastasis in inflammatory and noninflammatory breast cancers. Clinical Breast Cancer, 15(1), 37-42. Abstract below, free full text not available.

Inflammatory breast cancer is a rare and aggressive presentation of breast cancer. Bone is a common metastatic site in breast cancer, and bone-only metastatic disease is clinically considered to have a better prognosis than visceral metastasis. However, bone-only metastasis in IBC (bone-only IBC) has not been compared with bone-only metastasis in non-IBC (bone-only non-IBC) in terms of clinical features and outcome. Because of the intrinsically aggressive nature of IBC, we hypothesized that bone-only IBC has a poorer prognosis than does bone-only non-IBC.
We retrospectively identified patients with stage III primary diagnosed breast cancer who, between January 1997 and December 2012, had a first recurrence located only in the bone. Among the 197 patients that we defined as a study cohort, 50 patients had IBC and 147 patients had non-IBC. Progression-free survival (PFS) and overall survival (OS) from the date of recurrence were estimated using the Kaplan-Meier method, and patient characteristic groups were compared using the log-rank test.
OS did not differ significantly between the 2 groups (P = .2467), but a shorter PFS was seen in patients with bone-only IBC than in patients with bone-only non-IBC (P = .0357). Among patients with estrogen receptor (ER)-positive disease, a much shorter PFS was seen in bone-only IBC than in bone-only non-IBC (P = .0159).
Bone-only IBC has a poorer prognosis than does bone-only non-IBC, particularly in those with ER-positive tumors. We might need to consider more aggressive intervention (eg, chemotherapy) for IBC patients with ER-positive bone-only metastatic disease.