bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of eribulin with trasutuzumab for pretreated locally advanced or metastatic HER2-positive breast cancer.
Authors: Tsunoda Nobuyuki , Hattori Masaya , Murata Toru , Akahane Kazuhisa , Kamei Keitaro , Goto Yasutomo , Amemiya Takeshi , Nishimae Kazumi , Kubota Tomoyuki , Ito Yuko , Kurumiya Yasuhiro , Yoshihara Motoi , Nakanishi Kenichi , Kikumori Toyone , Ando Masahiko , Nagino Masato 
Published: September 2018

e12505 Background: Eribulin mesylate demonstrated a survival benefit in patients with locally recurrent or metastatic breast cancer who previously received 2 or more chemotherapy regimens. There are limited studies reported about the efficacy of eribulin with trastuzumab as first-line therapy for locally advanced or metastatic HER2-positive breast cancer. The aim of this study was to assess the efficacy and safety of eribulin with trastuzumab as late-line therapy for locally advanced or metastatic HER2-positive breast cancer. Methods: In this multicenter, phase II, single-arm study, patients with locally advanced or metastatic HER2 positive breast cancer who previously received at least one chemotherapeutic regimen, received eribulin at 1.4 mg/m2 intravenously (I.V.) on days 1 and 8 of each 21-day cycle with an initial trastuzumab dose of 8 mg/kg I.V. on day 1, followed by 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. The primary end point was ORR, and secondary end points included PFS and safety. Results: Thirty-six patients (median age: 60.5 years) were enrolled. The median number of prior treatment regimens was 4 (range, 1‐8). Twenty-two patients (61.1%) had received prior pertuzumab treatment, 10 patients (27.8%) had prior T-DM1. Patients received a median of 6 cycles of eribulin with trastuzumab (2-13 cycles). The ORR was 17% (CR 0, PR 6) with median PFS of 4.6 months (3.3-7.0 months). The clinical benefit rate was 33%. The most common Grade 3/4 treatment-emergent adverse events were neutropenia in 22 (61%) patients, peripheral neuropathy in 3 (8%; all Grade 3) patients, fatigue in 1 (3%) patients. Five (13.9%) patients had asymptomatic LVEF decline. However, no grade 3 LVEF decline or symptomatic congestive heart failure was observed. The reasons for treatment discontinuation were disease progression in 27 (75%) patients and adverse events in 8 (22%) patients. Conclusions: Eribulin with trastuzumab is an acceptable option in late-line treatment for locally advanced or metastatic HER2-positive breast cancer. Clinical trial information: 000012350.
Duration of second-line T-DM1 therapy: Is it associated with duration of first-line anti-Her2 therapy in metastatic HER2 + breast cancer?
Authors: Katz Daniela , Feldhamer Ilan , Greenberg-Dotan Sari , Hammerman Ariel 
Published: September 2018

e12512 Background: Tumors with HER2 overexpression usually respond to HER2-targeted therapies. Since the CLEOPATRA and EMILIA trials, a taxane plus trastuzumab and pertuzumab (TTP) are the first-line standard for the management of HER2 + metastatic breast cancer (MBC) and trastuzumab emtansine (TDM-1) is the second-line standard. Intrinsic subtypes existing within HER2+ tumors may impact the degree of a patient’s response to anti HER2 therapy; however HER2 subtyping for predicting response is still experimental and not in routine clinical use. In this retrospective population-based study, we aimed to assess whether duration of treatment (DOT) of second-line TDM1 is associated with the DOT of first-line TTP, and might serve as a hint for a HER2 subtype. Methods: Clalit Health Services (CHS) manages health care of 52% of the Israeli population. We identified 113 HER2+ CHS MBC patients, treated with TTP as first-line treatment that initiated TDM1 as second-line, until Dec. 31, 2016. Patient's (pts) demography, HER2 and HR status were recorded. A Cox proportional hazard model, stratified by HR status, adjusted for age and prior adjuvant trastuzumab, was used to explore the association between second-line and first-line DOT in HR positive and negative pts. Results: Pts baseline characteristics and DOT in first- and second-line treatment are presented in the table. A statistically significant association between DOT of both treatment lines was found in HR positive pts with a trend also in HR negative pts. Conclusions: The observed association between first- and second-line DOT, unrelated to hormonal status, may result from a primary characteristic of the intrinsic tumor subtype, that impacts acquired resistance. Longer observations in larger patient cohorts are required to confirm this observation. [Table: see text]
A real-world registry to evaluate HER2-directed therapy in Australian patients with metastatic breast cancer (MBC).
Authors: Lee Margaret , Lok Sheau Wen , Turner Natalie Heather , Day Daphne , Greenberg Sally , Green Michael , Foo Serene S. , Yip Desmond , Nott Louise M. , Gibbs Peter , De Boer Richard H. 
Published: September 2018

e12515 Background: The management and outcomes of HER2 positive MBC have dramatically evolved with the introduction of HER2-targeted therapies. However, limited data regarding the uptake, impact and safety of these treatments in the real-world context, prompted us to initiate a comprehensive registry across multiple settings in Australia. Methods: We examined the multisite electronic registry TABITHA (Treatment of Advanced Breast Cancer in the HER2 positive Australian Patient) to capture clinical data of consecutive patients diagnosed with HER2 positive MBC between Jan 2016-Jan 2017. Patient demographics, use and outcomes of treatment were explored. Results: An initial cohort of 74 patients was identified, 28 (38%) with de novo metastatic and 46 (62%) with relapsed disease. The median age at presentation with MBC was 57 years (range 27-83), with main metastatic sites being bone (n = 41, 55%), major organs (n = 40, 54%), locoregional (N = 26, 35%) and central nervous system (n = 13, 18%). In total, 64 (86%) patients had received first-line HER2 therapy, including trastuzumab plus pertuzumab (n = 48, 75%), trastuzumab alone (n = 10, 16%) and trastuzumab-emtansine (n = 6, 9%). Ten patients had not received any HER2 therapy, of which 8 received best supportive care alone, 1 received endocrine therapy, and 1 received anti-resorptive therapy. The median age of non-HER2 treated patients was 61 (range 44-81) and 40% were ECOG 2+ compared to 25% of patients receiving HER2 therapy (p = NS). First-line HER2 therapy had been discontinued in 20/63 (32%) patients, due to progressive disease (n = 18, 90%) or toxicity (n = 2, 10%). Median time to progression was 12.7+ months (range 2.0-81.9+). Conclusions: Whilst trials of HER2 directed therapies have demonstrated a substantial impact on survival outcomes for MBC with modest toxicity, a proportion of HER2 positive patients in routine care may not receive these agents. Poor performance status contributes to non-HER2 therapy use, however data collection is ongoing and other potential drivers will be further examined. Where HER2 directed therapies are used, the preliminary data indicates good activity with the majority of patients still currently on treatment.
CLIA validation of a novel HER2 FISH test involving image-based cell-sorting to recover pure tumor cell populations from formalin fixed paraffin embedded tissue.
Authors: Bischoff Farideh Z. , Gerber Amanda , Sero Valeria , Khurana Aditi , Ting Marc , Webb Judy , Sims Cynthe , Verma Suman , Medoro Gianni , Manaresi Nicolò , Gunn Shelly , Moore Mathew , Cotter Philip 
Published: September 2018

e12519 Background: The use of the DEPArray™ system to prepare pure tumor cell populations for more reliable and accurate downstream molecular sequence analysis has been previously demonstrated. To formally evaluate the utility of the DEPArray™ for sample preparation prior to molecular testing, we conducted a CLIA validation study to investigate the analytical performance of the instrument as well as accuracy in determining HER2 status in FFPE tumor specimens using a standard FISH assay. Methods: An initial cohort consisting of 93 FFPE samples (68 from Breast and 25 from Stomach) were selected based on defined inclusion criteria (tumor type and tumor content). For each sample, a single 50µm FFPE scroll was dissociated and then stained using fluorescently labeled Vimentin and Cytokeratin markers to distinguish between putative stromal and tumor populations, respectively. Following separation of these populations on the DEPArray™, a minimum of 100 single cells from each population was recovered and used for subsequent HER2 FISH testing. In addition, an H&E of each sample was evaluated by a Pathologist to confirm the presence of tumor content. Single-cell HER2-FISH analysis was then performed on the DEPArray™ processed samples to assess the number of signals present for each of the chromosome 17 and HER2 loci. Results were compared to the conventional tissue section FISH score. Results: Of the 93 specimens, 80 samples met pre-analytical acceptability criteria that were also confirmed by conventional methods to be either HER2-positive (n = 43) or HER2-negative (n = 37). Overall, a 95% concordance between HER2 results derived from the conventional as compared to the DEPArray™ method was observed. In addition, the instrument performance in terms of reproducibility and reliability was reported as 100%. Conclusions: DEPArray™ for preparation of FFPE-derived tumor cells was analytically validated and shown to yield high confidence in performing HER2-FISH analysis on recovered pure tumor cells. Current strategies to establish clinical utility and efficacy of this approach are underway for cases characterized as equivocal for HER2 or indeterminate by FISH.
Early-onset neutropenia-related events in eribulin monotherapy: A possible biomarker in the real world?
Authors: Watanabe Junichiro , Onozawa Yusuke 
Published: September 2018

e12529 Background: Eribulin mesylate (eribulin) showed antitumor activity via the anti-tubulin effect, and improved overall survival (OS) in HER2-negative (HER2-) metastatic breast cancer (MBC) patients without extending progression-free survival (PFS) in a phase 3 trial. On the other hand, according to the published data (Watanabe J, Springerplus, 2015), eribulin monotherapy improved OS in the clinical setting, and PFS is a possible surrogate for OS in HER2-, hormone receptor-positive (HR+) MBC patients. However, there is no practical biomarker for PFS in relation to eribulin monotherapy in patients with HER2-HR+MBC. Methods: Eribulin was administered according to the instructions in the package insert (1.4mg/m2 on days [D] 1 and 8, and a 21-day cycle [C]). The medical records of the patients who received eribulin monotherapy were reviewed. Results: From August 2011 to December 2016, 90 HER2-HR+MBC patients received eribulin monotherapy as daily practice at our institution, and 84 (93.3%) patients terminated their therapy. Lung and/or liver metastasis was observed at the induction of the therapy in 68 (86.7%) of the patients. The median relative dose of eribulin on C1D1 was 95.3% (1.33mg/body). Fever was observed during C1 in 23 (25.6%) patients, and grade (G) 3/4 neutropenia was observed on C1D8 in 28 (31.1%) patients. In contrast, only 4 (4.4%) patients developed febrile neutropenia within C1. Due to the delayed recovery of neutrophils, the second cycle of treatment was suspended in 8 (8.9%) patients. With regard to liver test abnormalities, an elevation of one grade in comparison to baseline, which resolved afterward without specific treatment, was observed during C1 in 24 (26.7%) patients. A multivariate Cox regression analysis revealed that G3/4 neutropenia on C1D8 and a delay of C2D1 were strong predictors of PFS (hazard ratio [HR] 0.53; p < 0.05, HR 0.42; p < 0.05, respectively). A chi-squared test revealed no statistically significant differences between the two subgroups in the relative dose on C1D1. Conclusions: This retrospective, observational study revealed that early-onset neutropenia-related events may be a biomarker for eribulin therapy that can be applied in the clinical setting.
The role of mitochondrial estrogen receptor β in relapse of breast cancer.
Authors: Kim Tae Hyun , Song In-Sung , Han Jin 
Published: September 2018

e12540 Background: Breast cancer is the most common non-skin cancer in women. Breast cancers are heterogeneous, and treatment by subgroup based on hormone receptor and HER2 made a significant difference in clinical outcomes. Several studies have reported that estrogen receptor beta (ERβ) decreases during tumor development in the breast epithelium. However, the role of ERβ in relapse and metastasis of breast cancer is poorly understood. Methods: In this study, we retrospectively studied 30 case breast carcinomas divided luminal, HER2, and triple negative subtype. Among them, patients relapsed within 5 years are 6 cases. The expression of ERβ gene in breast cancer tissues (30 cases) was estimated using a quantitative PCR, and other marker (ERα, HER2, PR etc) was measured anonymously in formalin-fixed paraffin-embedded tumor sections, by using specific antibodies. Results: A low level of ERβ expression and mitochondrial translocation of ERβ was associated with relapse/metastasis of breast cancer. The ERβ depletion resulted in resistance in response to tamoxifen treatment of MCF-7 breast cancer cells. Conversely, the overexpression of mitochondrial ERβ enhanced the cell death by treatment of tamoxifen in MCF-7 cells. We found that ERβ localizes to the mitochondria via the interaction with Grp75 and improves mitochondrial oxygen consumption rate and ATP production in breast cancer cells. Finally, we showed that ERβ level was a low in the breast cancer stem cells (CD24-CD44+ cells) compared with breast non-cancer stem cells (CD24+CD44- cells), whereas ERα level was a high. The overexpression of mitochondrial ERβ contribute to a decrease of sphere formation showing a tumorigenic ability. Conclusions: The mitochondrial ERβ contribute to suppress survival and stemness of cancer stem cells for relapse/metastasis, promising to the development of novel strategies for the treatment of breast cancer patients.
Identification of differentially expressed genes associated with clinical response after treatment of breast cancer skin metastases with imiquimod.
Authors: Rozenblit Mariya , Heguy Adriana , Chiriboga Luis , Loomis Cynthia , Darvishian Farbod , Egeblad Mikala , Shao Yongzhao , Adams Sylvia 
Published: September 2018

e12541 Background: Imiquimod, a Toll-like receptor 7 agonist, activates innate immunity and has a response rate of 20% in breast cancer skin metastases. Tumor regression is associated with increased tumor infiltrating lymphocytes and increased Th1 cytokines in tumor supernatant, however gene expression changes are unknown. This is the first report of gene expression changes induced by imiquimod treatment in breast cancer skin metastases. Methods: FFPE-extracted mRNA from 8 patients pre and post 8 weeks of imiquimod treatment was analyzed using Nanostring PanCancer Immune Profiling Panel. Gene expression and pathway analysis was conducted with nSolver 3.0 with clinical response as outcome, controlling for HER2 ER/PR status, with 5% significance level used. Results: In all patients, imiquimod was associated with upregulation of genes in innate immunity such as TLR7, IL-1, T-cell, B-cell, and NK related genes. Three patients had a clinical response after imiquimod. Forty-two differentially expressed genes were identified in responders vs. non-responders after imiquimod. Reponders had up-regulation of T cell (CD2, SPN), NK cell (KLRC2), B cell (CD48), lymphocyte (LY96), and IL-2 (IL2RG) related genes. The top upregulated pathways were cytotoxicity, NK cell function, and antigen processing. Pre-treatment, the responders had upregulation of TNF and IL-17 related genes (TNFRSF10B, IL17RA) compared to non-responders. Comparing pre-treatment to post-treatment, Imiquimod was associated with mRNA expression changes in 72 genes in responders vs non responders. The top upregulated genes involved activation of lymphocytes (SH2D1A), NK cells (KLRC2), DCs (CLEC4C), several chemokines, IL7R and immune regulators PLD1 and IRF5. Conclusions: Clinical response to Imiquimod treatment of breast cancer skin metastases is associated with upregulation of genes in innate immunity suggestive of an anti-tumor immune response. Inhibition of negative feedback by addition of PLD1 inhibitors may enhance treatment response. Understanding the genetic signature of imiquimod can enhance prediction of response and inform possible combination therapies in the future.
Use of everolimus in advanced hormone receptor–positive metastatic breast cancer in a multicenter national observational study.
Authors: Cottu Paul H. , Lardy-Cleaud Audrey , Frank Sophie , Le Saux Olivia , Chabaud Sylvie , Parent Damien , Pistilli Barbara , Debled Marc , Mailliez Audrey , Veyret Corinne , Petit Thierry , Uwer Lionel , Guiu Lahaye Severine , Chamorey Emmanuel , Ung Mony , Arveux Patrick , Guesmia Tahar , Augereau Paule , Simon Gaetane , Bachelot Thomas Denis 
Published: September 2018

e12548 Background: The everolimus-exemestane combination has been included in the International guidelines for advanced HR+ breast cancer (mBC) since the results of the Bolero-2 trial. Marketing authorization has been granted in France in July 2012 and reimbursement in Nov. 2014. Very few real life data of everolimus (EVE) use have been reported. Methods: All patients who initiated treatment for a newly diagnosed mBC between Jan. 2008 and Dec. 2015 in all 18 French Comprehensive Cancer Centers have been included in the real life ESME database, which collects retrospective data using a clinical trial-like methodology with quality assessments. Primary endpoint of the current analysis was to evaluate the incidence and indication of EVE use before and after marketing authorization and reimbursement Results: The ESME program included a total of 16,703 patients of which 9,921 had HR+/HER2- mBC. Median age at metastatic diagnosis was 62.0 year (range 23-96). Visceral metastases were present in 60.3% of cases. Only 4123 patients (41.6%) received endocrine therapy alone as first-line therapy, and 60% were deemed endocrine resistant Overall, 1,217 (12.3%) pts have received EVE during therapy as of Dec. 2015 (all lines). EVE was given as first line therapy in 117 pts (10% of all EVE pts and 1.2% of pts receiving a first line therapy). In 99/117 pts (85%) EVE was combined with exemestane. Before 2012, EVE was barely used and mostly within clinical trials. After 2012, use of EVE increased steadily (table). Percentages refer to the total of pts who received any kind of treatment during a given year of observation (e.g., 506/4435 pts took EVE in 2015). Median duration of EVE use was 6.0 months (0-65) as first line treatment and 3.9 months (0-65) in pretreated patients. Main causes of EVE cessation were recorded and will be detailed at the meeting. Conclusions: In this very large French national and representative cohort of HR+ HER2- mBC, EVE use rose quickly as soon as marketed. EVE was mostly used in pretreated mBC albeit in probably too advanced pts. These data underline the need for physician and patient education for oral therapies. [Table: see text]
Breast cancer and incidence of non-caseating granulomas diagnosed in PET avid chest lymphadenopahy.
Authors: Bechara Rabih , Rich Patricia , Parks Christopher , Bonta Dacian , Bonta Ioana 
Published: September 2018

e12549 Background: Breast cancer is known to metastasize to the lung parenchyma and lymph nodes. Most breast malignancies are clinically staged using radiographic modalities (e.g. PET scans). Importantly, several inflammatory disorders will present lymph node FDG-uptake on PET, which can be mistaken for breast cancer metastasis. This may alter staging and implicitly treatment for individuals within whom both undiagnosed autoimmune disorders and breast cancer co-occur. We aim to examine the frequency of non-caseating granulomas diagnosed in PET avid mediastinal/hilar nodes in patients with known breast cancer. Methods: Between March 2013 and December 2015, 46 women diagnosed with breast cancer were staged by PET-CT. Those with positive result in the mediastinum/hilum underwent linear endobronchial ultrasound (EBUS) for pathologic diagnosis and ensuing treatment Results: Of the 46 patients with avid mediastinal/hilar adenopathy, 31 (67%) had malignant cytology on EBUS; the remaining 15 had positive PET but negative cytology for malignancy. Twelve of the 15 patients with false positive PET had reactive lymph nodes, and 3 had non-caseating granulomas on cytology (see table). Twenty percent of the patients with negative cytology and positive PET had non-caseating granuloma, and 6.5 % of all patients with positive PET had non-caseating granulomas. Conclusions: To our knowledge, this study represents the largest cohort of breast cancer patients, where the incidence of non-caseating granulomas is investigated in PET-positive mediastinal/hilar nodes. We conclude that in selected patients, in addition to imaging, pathologic staging should be done. Also, the finding of non-caseating granulomas in these patients may either indicate an incidental diagnosis of early stage sarcoidosis, or an inflammatory reaction to the current treatment (sarcomatoid reaction). We also suggest that these patients should be followed for any manifestations of sarcoidosis. [Table: see text]
Chemotherapy to induce T-cell subpopulation changes in advanced breast cancer patients.
Authors: Comolli Giuditta , Torchio Martina , Franceschetti Benvenuto , Cassaniti Irene , Rapposelli Ilario , Marone Piero , Bertolini Alessandro , Baldanti Fausto , Danova Marco 
Published: September 2018

e12562 Background: Recent data suggest that some anti-cancer agents may generate a stimulation of the immune system that can account for additional clinical responses. In breast cancer (BC) the immunomodulation via chemotherapy (CT) opens possible clinical applications, but: a) the variability in the immune response requires a careful pt selection and b) monitoring immunocompetence in clinical routine still represents a technical challenge.Changes in sub-populations of cytotoxic (CD8+) T-cells (as reported in aging) are not well documented in cancer pts. Methods: We utilized multi-color immunophenotyping by flow cytometry (FCM) using a high-resolution whole-blood assay in 39 pts (median age 53; 34 - 74 yrs) with advanced BC undergoing first-line, standard-dose anthracycline/taxane-based CT and in 12 older healthy women, during a 6-months study, to analyze variations in CD8+ T-cells and the effects of CT on different T-cell sub-populations. Results: In all BC pts there was a consistent decrease in absolute numbers of lymphocytes, T-cells and CD8+ T-cells, starting from the first course and persisting during all the CT program. Among the T-cells, there was a lower CD8-/CD8+ ratio, persisting over 6 months, in pts compared to controls. The proportion of CD28-CD57+ cells also remained higher among pts throughout the sampling duration. The number of CD28+CD57- and CD28-CD5- cells decreased faster during CT than CD28+CD57+ and CD28-CD57+ cells, while only CD28-CD57- cells showed a significant reconstitutive capacity after 6 months.Anti-tumor CT in BC pts can produce clinical benefits also by restoring the responsiveness of T cells and by increasing the frequency and activation of tumor specific T-cells already present in blood before CT. Conclusions: Anthracycline/taxane-based CT is able to elicit changes in the pts immune system. These changes appeared to be pronounced in BC pts, with senescent CD8+ T-cells playing an important role. The pre-treatment condition was not restored after 6 months of CT. Multi-parameter FCM is a powerful tool for detailed analysis of the immune dysfunctions during CT and it will also help the development of combined schedules of CT plus new immunotherapeutic agents.