bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-15-13: CDK8 inhibition potentiates anti-ER and anti-HER2 therapies in breast cancer
Authors: McDermott Martina S , Lim Chang-uk , Chen Mengqian , Chumanevich Alexander , Catroppo James F , Gyorffy Balazs , Oliver David , Roninson Igor B , Broude Eugenia V 
Published: May 2015

Abstract
CDK8, along with its paralog CDK19, is a cyclin dependent kinase which, in contrast to other members of the CDK family does not regulate cell cycle progression. CDK8 acts as a pleiotropic transcription regulator potentiating the induction of transcription by several transcription factors. Immunohistochemical staining of breast tissue arrays and bioinformatics analysis of gene expression microarray data of breast cancer patients revealed that CDK8 is overexpressed in breast cancer and that higher CDK8 expression correlates with the failure of systemic therapy. Small-molecule selective inhibitors of CDK8 and CDK19 (Senexin A and Senexin B) inhibited the mitogenic effects of estrogen and estrogen-dependent transcription in estrogen receptor (ER)+ breast cancer cell lines. CDK8/19 inhibitors had a cytostatic effect on different ER+ cell lines, and this growth inhibition was synergistic with the effect of the anti-estrogen fulvestrant, particularly in ER+ cell lines resistant to estrogen deprivation. Some of the ER+ cell lines sensitive to CDK8/19 inhibition also express HER2, and therefore we tested CDK8/19 inhibitors in combination with the HER2 and EGFR tyrosine kinase inhibitor lapatinib and an anti-HER2 monoclonal antibody, a biosimilar of trastuzumab. CDK8/19 inhibition produced a synergistic decrease in cell growth with both HER2 inhibitors; this effect was especially pronounced with a trastuzumab biosimilar. Surprisingly, the synergistic effect with HER2 inhibitors was observed in both ER+ HER2+ and ER-HER2+ cell lines, suggesting an effect on a HER2-complementing molecular target other than ER. Interestingly, CDK8/19 inhibition also synergized with trastuzumab biosimilar in a breast cancer cell line that exhibits innate resistance to trastuzumab, suggesting that CDK8/19 inhibition can overcome trastuzumab resistance in breast cancer. These results suggest that combining anti-estrogen and anti-CDK8 therapy may be more effective than conventional hormone therapy for ER positive breast cancer and that combining anti-HER2 and anti-CDK8 therapy is a rational potential treatment for HER2+ breast cancer, regardless of ER status or sensitivity to trastuzumab.
Citation Format: Martina S McDermott, Chang-uk Lim, Mengqian Chen, Alexander Chumanevich, James F Catroppo, Balazs Gyorffy, David Oliver, Igor B Roninson, Eugenia V Broude. CDK8 inhibition potentiates anti-ER and anti-HER2 therapies in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-13.
Abstract P4-15-14: Preclinical data of SYD985 support the clinical investigation of this novel anti-HER2 antibody-drug conjugate in breast cancer patients with low levels of HER2 expression
Authors: Verheijden Gijs , Beusker Patrick , Ubink Ruud , Lee Miranda van der , Groothuis Patrick , Goedings Peter , Egging David , Timmers Marco , Dokter Wim 
Published: May 2015

Abstract
SYD985 is a novel anti-HER2 antibody-drug conjugate (ADC) in development for breast cancer. The ADC consists of three parts: i) the monoclonal antibody trastuzumab, ii) a linker that can be cleaved by tumor-resident proteases at the dipeptide valine-citrulline (vc) motif, and iii) the prodrug seco-DUocarmycin-hydroxyBenzamide-Azaindole. The average ‘drug to antibody ratio’ (DAR) of this ADC, also named trastuzumab vc-seco-DUBA, is ∼2.8. After antibody-mediated binding of SYD985 to its molecular target HER2 on the surface of tumor cells, the ADC is internalized. Subsequently, the active duocarmycin is released and binds to DNA in the minor groove, followed by alkylation of the DNA and killing of the tumor cells.
In vitro and in vivo experiments were performed to (directly) compare various pharmacodynamic and pharmacokinetic properties of SYD985 with those of the most progressed (marketing-approved) HER2-targeting ADC, i.e. ado-trastuzumab emtansine (T-DM1). T-DM1 is currently indicated for second line treatment of breast cancer patients overexpressing HER2 tumor tissue.
In in vitro experiments, SYD985 shows potencies similar to T-DM1 in cell lines expressing HER2 at high levels (IHC HER2 3+), whereas SYD985 is significantly more potent compared to T-DM1 in cell lines expressing low HER2 levels (IHC HER2 2+ or 1+). In line with these results, SYD985 has superior efficacy compared to T-DM1 in xenograft models in which patient-derived breast cancer tumor tissue with low HER2 levels (IHC HER2 2+ or 1+/FISH-) have been used.
Pharmacokinetic experiments (in vitro and in vivo) have revealed that whereas in mice SYD985 has limited stability, in cynomolgus monkey SYD985 is very stable. Excellent stability in vitro is also observed in human plasma. Moreover, after i.v. administration of SYD985 in the cynomolgus monkey the amount of free toxin (DUBA) detected in the monkey plasma is many-fold lower than levels reported for the toxin (DM1) released from T-DM1.
Resuming, the preclinical data of SYD985 support clinical studies to investigate whether SYD985 has benefit in cancer patients with moderate or even low HER2 levels of the tumor tissue.
Citation Format: Gijs Verheijden, Patrick Beusker, Ruud Ubink, Miranda van der Lee, Patrick Groothuis, Peter Goedings, David Egging, Marco Timmers, Wim Dokter. Preclinical data of SYD985 support the clinical investigation of this novel anti-HER2 antibody-drug conjugate in breast cancer patients with low levels of HER2 expression [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-14.
Abstract P4-15-22: The ASCO/CAP guideline update for HER2 testing increases the number of breast cancer patients eligible for HER2-targeted therapy
Authors: Giacomazzi Juliana , Hartmann Carolina R , Paskulin Diego D , Rivero Luis Fernando , Caleffi Maira , Pasqualotto Alessandro C , Graudenz Marcia S , Rosa Daniela D 
Published: May 2015

Abstract
Background: The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) published, in Nov/2013, the interpretive guidelines for HER2 testing of breast cancer patients. This aimed to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer. The former version of these criteria was written in 2007. Objectives: to compare the HER2 immunohistochemical (IHC) analysis using the 2007 versus 2013 algorithms in a cohort of breast cancer cases diagnosed in a single institution in Southern Brazil. The cases were previously classified as HER2 1+ or 2+, using the 2007 criteria. Methods: the sample included 100 invasive breast cancer cases. The HercepTest (Dako, Denmark) was used for determination of HER2 expression. The HER2 testing was analyzed independently by two pathologists. The FISH analysis was done using a HER2/D17Z1 probe set. Preliminary Results: The HER2 IHC interpretation changed in 11/69 (15.9%) cases: 8.7% negative or equivocal cases by the 2007 guidelines were positive by the 2013 classification and 7.2% of HER2 1+ cases became equivocal (p&lt;0.001; x2 test). The FISH analyses are ongoing. Conclusion: The 2013 ASCO/CAP guidelines resulted in less negative cases and in more equivocal (requiring reflex testing) and positive tests. Applying the ASCO/CAP 2013 guidelines resulted in a significantly increase of breast cancer patients eligible for HER2-targeted therapies.
Citation Format: Juliana Giacomazzi, Carolina R Hartmann, Diego D Paskulin, Luis Fernando Rivero, Maira Caleffi, Alessandro C Pasqualotto, Marcia S Graudenz, Daniela D Rosa. The ASCO/CAP guideline update for HER2 testing increases the number of breast cancer patients eligible for HER2-targeted therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-22.
Abstract P5-02-12: Concordance between semiquantitative immunohistochemical assay and oncotype DX RT-PCR assay for estrogen and progesterone receptors
Authors: Novas Patricia , Galve Elena , Fernández Sara , Sala Maria Ángeles , Arévalo Alberto , Arango Juan , López de San Vicente Borja , Fernández Seila , Zumárraga Ane , Martínez del Prado Purificación 
Published: May 2015

Abstract
Introduction: Estrogen receptor (ER) and progesterone receptor (PR) expression are generally determined by semiquantitative immunohistochemistry (IHC) as recommended in the clinical practice guidelines of the American Society of Clinical Oncologists. This method may be subject to variability because of differences in fixation, ER antibody clones, as well as to immunostain interpretation and use of arbitrary cut-off points. Materials and methods: We identified 72 breast cancer cases at Basurto University Hospital from 1 September 2012 to 31 May 2014 that have been analyzed by Oncotype DX with reporting on ER/PR expression levels by RT-PCR (Genomic Health Inc, Redwood City, CA). According to the company’s report, a tumor is considered as ER positive with expression units of &gt;=6.5 and PR positive with expression units of &gt;=5.5. Oncotype DX is a commercial assay that predicts tumor recurrence in node-negative ER-positive breast cancers. It is a reverse transcription-polymerase chain reaction (RT-PCR) based assay that analyzes the expression of 21 genes (16 cancer-related and 5 control genes) to provide a distant disease recurrence score ranging from 0 to 100. At our institution, hormone receptors by IHC were analyzed on corresponding surgery breast specimens at the time of initial diagnosis. They were evaluated by IHC on formalin-fixed paraffin-embedded tissue, between 8-72 hours. ER was assessed using Roche antibody clone SP1 and PR was assessed using antibody clone 1E2. Percentage of positive nuclei was determined by visual microscopic estimation: &lt;1 negative and ≥1 positive. We compared our semiquantitative method of reporting ER and PR status based on IHC to the RT-PCR hormone receptor results from Genomic Health. Results: There was 100% concordance between IHC and the RT-PCR assay for estrogen receptor status. PR findings between IHC and Oncotype Dx revealed a lower concordance (82%) than for ER. RT-PCR was negative in 10 (14%) cases in which IHC was positive. Pearson correlation coefficient for PR was 0.313. Although our results demonstrated high concordance between IHQ and Oncotype Dx for ER, our data showed poor concordance for PR.
Citation Format: Patricia Novas, Elena Galve, Sara Fernández, Maria Ángeles Sala, Alberto Arévalo, Juan Arango, Borja López de San Vicente, Seila Fernández, Ane Zumárraga, Purificación Martínez del Prado. Concordance between semiquantitative immunohistochemical assay and oncotype DX RT-PCR assay for estrogen and progesterone receptors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-02-12.
Abstract P5-04-14: Decreased functions of natural killer cells in peripheral blood of advanced triple negative breast cancer patients
Authors: Park In Hae , Kong Sun-Young , Kang Joo Hyun , Mo Hye Jin , Kim Tae Sik , Lee Keun Seok , Ro Jungsil 
Published: May 2015

Abstract
Background : Natural killer (NK) cells are a major player in innate immune response. Two distinct NK cell subsets with different functions as the strongest cytotoxic activity (CD56dimCD16+) or cytokine production (CD56brightCD16+/-) have been known. In this study, we evaluated the phenotypic and functional difference of NK cells in peripheral blood (pB) from the patients who had advanced triple negative (TN) breast cancer compared to healthy controls.
Methods : We enrolled advanced triple negative (TN) breast cancer patients treated at the National Cancer Center, Korea between March 2012 and March 2014. Healthy controls who visited for health screening were recruited at the same time period and peripheral blood (pB) samples were collected. In patient groups, pB was sampled either prior to the initiation or during the courses of chemotherapy. Then, patients were retrospectively classified into two groups as follows; non-responders (the group A) and responders (the group B) to the treatment. NK cells were isolated from peripheral blood mononuclear cells (PBMC) and analyzed based on their expression of CD56 and CD16. We looked at cytotoxic activity of pB NK cells against K562 cell line and measured CD107a expression as a parameter of NK cell activation.
Results : The absolute numbers of lymphocytes and NK cells per cubic millimeter of pB were similar among healthy controls (N=24), the group A (N=16), and the group B (N=21). There was no significant difference in the proportion of pB NK cell subsets among three groups except CD56brightCD16+/- subset which was significantly higher in the group B compared to healthy controls (P=0.0014). Even in the presence of similar proportions of NK subsets, the activities of CD56dimCD16+ NK cells measured by CD107a expression were significantly lower both in the group A (P=0.0023) and in the group B (P=0.0127) compared with those of control group. The activities of CD56dimCD16+ NK cells were not different between group A and B. In the case of CD56brightCD16+/- NK cells, CD107a positivity was significantly lower in the group A compared with controls (P=0.0068) and group B (P=0.0465).
Conclusions : Our data suggested that cytolytic functions of NK cells were significantly decreased in advanced TN breast cancer patients compared with those of healthy controls despite a similar proportion of NK cell subsets in pB.
Citation Format: In Hae Park, Sun-Young Kong, Joo Hyun Kang, Hye Jin Mo, Tae Sik Kim, Keun Seok Lee, Jungsil Ro. Decreased functions of natural killer cells in peripheral blood of advanced triple negative breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-04-14.
Abstract P5-07-01: Granulin, a novel STAT3-interacting protein, promotes breast cancer tumorigenicity
Authors: Yeh Jennifer E , Kreimer Simion , Walker Sarah R , Richardson Andrea , Ivanov Alexander R , Frank David A 
Published: May 2015

Abstract
Since the neoplastic phenotype of a cell is largely driven by its gene expression patterns, increasing attention is focused on transcription factors that regulate critical mediators of tumor formation and metastatic progression like the oncogenic transcription factor, signal transducer and activator of transcription 3 (STAT3). Whereas normal cells have transient activation of STAT3 due to tight control by negative regulators, cancer cells frequently have inappropriate constitutive activation of STAT3 which drives increased expression of genes involved in tumorigenesis. However, little is known about proteins that interact with STAT3 to modulate its function. To identify novel STAT3-interacting proteins, we performed liquid chromatography tandem mass spectrometry-based profiling of STAT3-containing complexes immunoprecipitated from the triple-negative breast cancer cell lines MDA-MB-468 and SUM159PT, which have constitutively active STAT3. We identified granulin (GRN) as a novel STAT3-interacting protein and validated the STAT3-GRN interaction in breast cancer cells by co-immunoprecipitation. To investigate the functional effect of GRN on STAT3 activity, we silenced GRN using small interfering RNA. We found that GRN was necessary for constitutive and maximal cytokine-induced STAT3 transcriptional activity in breast cancer cells. GRN modulated cytokine-induced STAT3 function by enhancing STAT3 DNA binding and increasing the time-integrated amount of STAT3 activation and nuclear translocation. Silencing GRN mirrored the effect of silencing STAT3 on reducing the viability, clonogenesis, and migratory capacity of triple-negative breast cancer cells. Furthermore, GRN mRNA levels were significantly and positively correlated with STAT3 gene expression signatures indicative of STAT3 activation as well as with reduced overall survival in breast cancer patients. These studies used a proteomics approach to identify GRN as a novel STAT3 interacting protein that may serve as an important prognostic biomarker and potential therapeutic target in breast cancer.
Citation Format: Jennifer E Yeh, Simion Kreimer, Sarah R Walker, Andrea Richardson, Alexander R Ivanov, David A Frank. Granulin, a novel STAT3-interacting protein, promotes breast cancer tumorigenicity [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-07-01.
Abstract P5-09-02: The CYP19 RS4646 polymorphism is related to the prognosis of stage I–II and operable stage III breast cancers
Authors: Shao Xiying , Wang Xiaojia , Zheng Yangbing , Huang Ping , Huang Jian 
Published: May 2015

Abstract
Background: Aromatase, encoded by the CYP19 gene, catalyzes the final step of the conversion of androgens to estrogens. In premenopausal women, estrogen is mainly produced by the ovary, while in postmenopausal women, aromatization of androgen in extragonadal tissue, for example, adipose tissue, is the main source. Given the critical role of CYP19 in estrogen synthesis and the association of clinical outcome with rs4646 polymorphism, we investigated the clinical relevance of CYP19 rs4646 genotypes in early breast cancer.
Methods: Genotype for CYP19 rs4646 variants was performed on 406 Chinese women with early breast cancer. Associations were examined between rs4646 genotypes with histopathological characteristics and disease-free survival.
Results: In patients younger than 50 years, women who are homozygous for the minor allele (AA) have a longer disease-free survival (DFS)compared with those carrying the major allele(CC or AC) (87 months versus 48.7 months; HR 0.560; 95CI 0.318-0.985; P =0.041). This differences was further demonstrated by a multivariate analysis (HR 0.456; 95CI 0.249-0.836; P=0.011). Conversely, the same variants(AA) were found to be associated with a poorer DFS in women with age above 50 years (AA versus AC or CC: 38.9months versus 79.7 months; HR 2.758; 95% CI: 1.432-5.313; P=0.002). Furthermore, the differences was proved by the COX proportional hazards model (HR 2.983; 95CI 1.494-5.955; P=0.002).
Conclusions: The present study indicates that CYP19 rs4646 polymorphism is associated with DFS in early breast cancer and that the prognosis index of the homozygous for the minor allele (AA) may depend on circulating estrogens levels due to the different age. The founding is novel, if confirmed in a larger prospective independent cohort, rs4646 genotypes may provide useful information for routine management in breast cancer.
Citation Format: Xiying Shao, Xiaojia Wang, Yangbing Zheng, Ping Huang, Jian Huang. The CYP19 RS4646 polymorphism is related to the prognosis of stage I–II and operable stage III breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-09-02.
Abstract P5-10-17: Evaluation of PgR status by immunohistochemistry may be inferior to PgR results by Oncotype DX for assessing the recurrence risk in ER+/HER2- breast cancer with low or intermediate tumor proliferation
Authors: Sinn Peter , Kriegsmann Mark , Felten Ute , Wacker Jürgen , Schneeweiss Andreas , Varga Zsuzsanna 
Published: May 2015

Abstract
Background: Loss of progesterone receptor expression is known to be a predictor of Luminal-B subtype, and is of independent prognostic significance in luminal type breast cancer. However, the threshold of PgR status in IHC has been subject to debate, and the PgR status as reported by IHC not infrequently is at variance with the PgR result as reported by the Oncotype DX (ODX) assay.
Methods: We retrospectively reviewed tumor IHC and ODX data from resection specimens with ER+/HER2- breast cancer, and low to intermediate Ki-67 proliferation rates (Ki-67 &lt; 30%). A total of 74 specimens were re-analyzed, all from resection specimens that had been selected for ODX assay for the purpose of planning of adjuvant chemotherapy, from two institutions (Univ. Heidelberg, Germany, and Univ. Zurich, Switzerland). PgR expression of &lt; 10% using IHC (clone PgR636, Ventana and Dako systems) or PgR values of &lt; 5,5 in ODX assay were considered negative.
Results: All cases were positive for ER by IHC and ODX, and 20% were negative for PgR by ODX assay. This compared to only 8% of negativity by IHC, but all except one case negative for PgR by IHC were also correctly identified as PgR negative by ODX. Median ODX recurrence score (RS) was 35 for PgR negativity by ODX assay, as compared to 30 for negative PgR status by IHC. For positive PgR status, median RS was calculated as 15 vs. 17 by ODX vs. IHC. Risk categories by ODX were high (RS &gt;= 31) in 9 cases with negative PgR status by ODX, but only 3 of these high risk cases were negative for PgR by IHC. Median Ki-67 values were 22.5 for PgR negative cases by ODX as compared to 15 for PgR negative cases by IHC. Similar results were obtained when a higher PgR threshold of 20% was applied to IHC results.
Conclusions: In luminal type breast cancers, the evaluation of PgR status by IHC may underestimate the proportion of PgR negative cases and did not identify most cases of tumors with a high risk of recurrence. This may be caused by an overly high sensitivity of PgR status in routine automated immunohistochemistry.
Citation Format: Peter Sinn, Mark Kriegsmann, Ute Felten, Jürgen Wacker, Andreas Schneeweiss, Zsuzsanna Varga. Evaluation of PgR status by immunohistochemistry may be inferior to PgR results by Oncotype DX for assessing the recurrence risk in ER+/HER2- breast cancer with low or intermediate tumor proliferation [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-10-17.