bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P1-15-05: GSTP1 polymorphism is associated with chemotherapy induced neuropathy
Authors: Miltenburg NC , Opdam M , Winter M , van Geer M , Oosterkamp HM , Boogerd W , Linn SC 
Published: August 2014

Abstract
Background: Peripheral neuropathy is a common and potentially debilitating side-effect of microtubule-stabilizing agents like docetaxel and is characterized by sensory symptoms like numbness, tingling and burning pain. Docetaxel induced neuropathy may occur in up to 37% of patients and can be dose limiting, thus potentially reducing its chemotherapeutic efficacy. Doxorubicine has occasionally been described to be associated with neuropathy.
With this background we investigated the role of various single nucleotide polymorphisms (SNPs) to predict chemotherapy-induced neuropathy. The exploration of SNPs and an association with incidence or severity of neuropathy is important, because it can result in identifying individuals being at higher risk of neurotoxicity.
Methods: The MATADOR study is a prospective, non-blinded randomized phase II/III trial for patients with invasive breast cancer, comparing TAC (docetaxel 75 mg/m2 as 1 hour i.v. infusion q 3 weeks, in combination with doxorubicin and cyclophosphamide for 6 cycles) with AC dose dense (doxorubicin and cyclophosphamide q 2 weeks)(ISRCTN61893718).
In total 180 interesting SNPs were selected that are involved in metabolism, distribution and excretion of drugs and tested on DNA that was isolated from tumor or from tumor surrounding tissue. We selected 20 SNPs for further analyses because of reported associations with chemotherapy-induced neuropathy (see table).
In the first analysis DNA of 45 patients was analyzed as a pilot, comparing DNA of 23 neuropathy patients with that of 22 controls. The primary hypothesis was to identify SNPs associated with NCI-CTC grade ≥2 neuropathy.
Results: Interim toxicity data from the MATADOR study demonstrated that 30 of 580 patients had grade ≥2 neuropathy. GSTP1 114Ala/114Val genotype was associated with grade ≥2 neuropathy. Twelve out of 14 (86%) patients with this genotype had chemotherapy-induced neuropathy compared to 11 out of 31 (35%) without this genotype (chi-square test p = 0.002).
Conclusion: We found a correlation between GSTP1 114Ala/114Val genotype, involved in detoxification, and development of grade ≥2 neuropathy during treatment with chemotherapy. Updated results will be presented at the meeting.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-05.
Abstract P2-01-01: Establishment and validation of circulating tumor cell-based prognostic nomograms in 497 first-line metastatic breast cancer patients
Authors: Giordano A , Reuben JM , Egleston BL , Hajage D , Hortobagyi GN , Cristofanilli M , Pierga J-Y , Bidard F-C 
Published: August 2014

Abstract
Background: Several prognostic clinical and pathological characteristics have been reported to be independently associated with survival in metastatic breast cancer (MBC). Circulating tumor cells (CTCs) isolated by CellSearch® from peripheral blood of MBC patients was shown to be an additional strong independent prognostic factor for survival and progression of disease. The aim of this study was to combine CTC and other predictors in a nomogram that would allow clinicians to assess, on an individual basis, the prognosis of patients starting first-line chemotherapy for MBC.
Patients and Methods: CTCs were counted before the start of treatment using the US Food and Drug Administration–cleared CellSearch® technology. We used a training set of 237 MBC patients starting a first line chemotherapy from the MD Anderson Cancer Center (MDACC, Houston, TX, USA), and nomograms were established to calculate the predicted probability of overall survivals (OS) at 1, 2 and 3 years. These nomograms were externally validated using an independent data set of 260 patients starting a first line chemotherapy from the prospective Institut Curie 2006–04 study (Paris, France). Discriminatory ability of the models was assessed using Harrell's c-statistic examining the model in the training sample (U.S. data) and the validation sample (French data). Accuracy of the nomograms was assessed both within the training sample and the validation sample via calibration plots at 1, 2 and 3 years. Covariates computed in the model were: age, subtype of disease, presence of visceral metastasis, bone metastasis, performance status, and CTCs.
Results: Table1 describes patient characteristics. Median follow-up was of 24.5 and 29 months, respectively in the MDACC and Institut Curie. The C-statistics for OS was 0.7338 in the training set and 0.7229 in the validation set. For the calibration plots, we averaged Cox predictions at two years within the quintiles of the ordered predictions. Within each quintile, we also estimated the unadjusted probability of death using Kaplan-Meier survival estimators. We then plotted unadjusted versus model average predictions at 1, 2 and 3 years. The nomograms discriminated OS prediction at 1, 2 and 3 years very well.
Conclusions: Patients with first-line MBC present a wide range of survival duration, and our ability to assess prognosis and predict risks of progression and death on the basis of clinic-pathologic findings is limited. The validated nomograms represent an important tool for estimating prognosis, support treatment-decisions and clinical trial stratification in MBC.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-01-01.
Abstract P2-01-02: Circulating Tumor Cells (CTC) may Express HER2/neu in Patients With Early HER2/neu Negative Breast Cancer – Results of the German SUCCESS C Trial
Authors: Jaeger BAS , Rack BK , Andergassen U , Neugebauer JK , Melcher CA , Scholz C , Hagenbeck C , Schueller K , Lorenz R , Decker T , Heinrich G , Fehm T , Schneeweiss A , Lichtenegger W , Beckmann MW , Pantel K , Sommer HL , Friese K , Janni W 
Published: August 2014

Abstract
Background: There is growing evidence that the HER2/neu-status of distant metastases or minimal residual disease in blood and bone marrow may differ from the primary tumor in patients with breast cancer. The HER2/neu-status of CTCs was prospectively evaluated in patients with HER2/neu negative primary breast cancer randomized into the German multicenter SUCCESS C study.
Methods: The SUCCESS C trial is a randomized Phase III study comparing FEC-Docetaxel (FEC-Doc) vs. Docetaxel-Cyclophosphamid (DC) as well as 2 years of a lifestyle-intervention in patients with early, HER2/neu negative, node positive or high-risk node negative primary breast cancer.
As part of the translational research program, 23ml peripheral blood were drawn after adjuvant chemotherapy. In 505 samples, the prevalence of CTCs and their HER2/neu-status were assessed using the CellSearch System (Veridex, USA). After immunomagnetic enrichment with an anti-Epcam-antibody, cells were labelled with anti-CK8/18/19 and anti-CD45 antibodies. A fluorescein conjugate antibody with anti-CK-Fluorescein Isothiocyanate (FITC) was used for HER2/neu phenotyping. The cut-off for CTC-positivity was ≥ 1 CTC and for HER2/neu ≥ 1 CTC with strong HER2/neu-staining (+++).
Results: 26,9% of pts (n = 136) were positive for CTCs (mean 1.78; range 1–7; median = 1). The number of detected CTC was distributed as follows: 1 CTC (n = 76; 55.9%), 2 CTCs (n = 35; 25.7%), 3 CTCs (n = 13; 9.6%), 4 CTCs (n = 7; 5.2%) and ≥ 5 CTCs (n = 5; 3.7%). HER2/neu staning of CTCs was not detectable or weak in 26.5% (n = 36) and 4.4% (n = 6) of CTC positive patients respectively and therefore categorized as HER2/neu negative. In 32.4% of the CTC-positive patients (n = 44), we detected moderate and in 36.8% (n = 50) strong HER2/neu-staining of ≥ 1 CTC per sample. No association was found between CTCs or the HER2/neu-status of CTCs with tumor size, histopathological grading, hormone receptor status or axillary lymph node involvement.
Conclusions: The data of this trial confirm previous findings that patients with HER2/neu negative primary breast cancer can show HER2/neu positive minimal residual disease. These results underline the importance of frequent HER2/neu determination during follow up and disease progression. Survival data within the Success C trial will give further insight into the tumor biology of HER2/neu negative disease.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-01-02.
Abstract P2-01-10: Immunocytochemistry staining for estrogen and progesterone receptor in circulating tumor cells: Concordance between primary and metastatic tumors.
Authors: Bischoff FZ , Pham T , Wong KL , Villarin E , Xu X , Kalinsky K , Mayer JA 
Published: August 2014

Abstract
Introduction: Estrogen (ER) and progesterone receptor (PR)) status is recommended by immunohistochemistry (IHC) and is considered standard practice for selection of treatment options in all breast cancer patients. Because biopsy is not often feasible in every patient presenting with recurrent and/or metastatic disease, circulating tumor cells (CTCs) offer an attractive alternative source of tumor tissue for determining ER/PR status. In addition, CTCs enable monitoring for more effective course of treatment.
Experimental Design: Twenty ml of peripheral blood was collected prospectively from 34 patients diagnosed with late stage metastatic/recurrent breast cancer. CTCs were isolated using the microfluidic OncoCEE platform. A cocktail of antibodies was utilized for CTC capture, and detection was accomplished with an expanded anti-cytokeratin (CK) cocktail mixture and anti-CD45. ER/PR protein expression was assessed by immunocytochemistry (ICC) on CK+/CD45- CTCs captured directly within the microchannel and then compared to IHC performed on the primary and/or metastatic tumor.
Results: CK+/CD45−/DAPI+ cells were detected in 22 of 34 (65%) patients with late stage breast cancer and assessed for ER/PR immunocytochemistry. Among the 22 cases with one or more CTCs, a concordance of 75% (15/20) and 90% (9/10) in ER/PR status between primary and metastatic tumor was observed, respectively. An overall concordance of 86% (19/22) was achieved. Five cases were discordant based on primary tissue alone; however, two of these cases are concordant when compared to the metastatic biopsy. Thus, only three cases were found to be discordant: all three were positive by IHC on the primary and/or metastatic tumor but negative by CTCs and all three had relatively low numbers of CTCs detected.
Conclusions: There is significant heterogeneity of ER/PR protein expression in CTCs and primary/metastatic tumor biopsy. In addition, hormonal status may change over time due to therapy. ER/PR ICC on CTCs using the OncoCEE platform is shown to be feasible, with high concordance (86%) as compared to primary and/or metastatic biopsy (by IHC). The significance of heterogeneity at the ER/PR protein level in CTCs related to the prognosis and predictive response to anti-estrogen therapy needs further evaluation in larger prospective clinical trials.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-01-10.
Abstract P2-01-13: Prognostic value of Circulating Tumor Cells count at progressive disease after first line chemotherapy metastatic breast patients in a large prospective multicenter trial including serum tumor markers (IC 2006–04 study)
Authors: Pierga J-Y , Hajage D , Bachelot T , Delaloge S , Brain E , Campone M , Asselain B , Cottu PH , Dieras V , Bidard F-C 
Published: August 2014

Abstract
Background: The IC 2006–04 study included prospectively 267 metastatic breast cancer patients before the start of first line chemotherapy. We previously reported and confirmed the prognostic and predictive of CTC counts before the start of treatment and after 3–4 & 6–9 weeks of treatment (Pierga, JY SABCS 2010, Ann Oncol 2012). We report here the results of the last CTC count performed at tumor progression (i.e. end of first line chemotherapy).
Methods: Patients were included in the study from 06/07 to 9/09. CTC were counted by the CellSearch® system at tumor progression (clinical and/or radiological progression).
Results: 211 patients experienced a tumor progression at time of final data analysis and the planned CTC count has been performed in 61 patients. High CTC count (≥5 CTC/7.5ml) at progression was observed in 22 patients (36%) and was associated with elevated Cyfra 21–1 and ALP and was not associated with elevated CEA, CA 15–3, LDH, the elapsed progression-free survival, the onset of new metastasis. No CTC was detected at tumor progression in the 5 patients with HER2+ disease, in line with our previous results. The prognostic markers for overall survival at tumor progression were high CTC count (median overall survival 8 vs 19 months, p = .0006) and elevated Cyfra 21–1 (p = .001). Other serum markers (CEA, CA15-3, ALP, LDH) and tumor subtypes had no prognostic value at univariate analysis. At multivariate analysis, the two prognostic factors for overall survival were high CTC count (RR = 2.3 p = 0.03) and elevated Cyfra 21–1 (RR = 3.6 p = 0.02).
Conclusion: In the prospective IC 2006–04 study, among the different markers tested at tumor progression during the first line chemotherapy for metastatic breast cancer, high CTC count and elevated Cyfra 21–1 levels were the only two independent prognostic markers for overall survival.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-01-13.
Abstract P2-04-08: Targeted Expression of the Human Chaperone BAG3 to the Murine Mammary Gland Dysregulates Mammary Gland Development and Differentiation By Unrestricted Expansion of Luminal Cells
Authors: Virador VM , Casagrange G , Raafat A , Callahan R , Kohn E 
Published: August 2014

Abstract
BAG3 is a pro-survival pro-invasion chaperone. We hypothesized that human BAG3 overexpression in murine breast would contribute to mammary tumorigenesis. We generated transgenic mice ectopically expressing hBAG3 in the mammary gland under the control of the Mouse Mammary Tumor Viral promoter (MMTV-hBAG3). hBAG3 was expressed in luminal cells throughout the ductal tree in multiple transgenic lines. Targeted expression of hBAG3 dysregulated mammary gland development by both increasing proliferation and differentiation. hBAG3 mammary glands had increased epithelial elongation at 5 weeks of age, premature glandular differentiation at 10 weeks, and features of ductal hyperplasia at week 13 with increased Ki67 and p-Histone H3 in the luminal compartment. At week 13 hBAG3 induced acinar differentiation. BAG3 pro-survival gain of function was recapitulated post-partum with delayed involution. Mammary glands of MMTV-hBAG3 had alveolar persistence three days after forced involution where non-transgenic controls demonstrated typical involution-driven apoptosis and remodeling. We crossed heterozygous MMTV-hBAG3 to WAP-Int3 mice with absent alveolar development in pregnancy. hBAG3 caused alveolar budding in the WAP-Int3 background. We hypothesized hBAG3 gain of function in the mammary gland would promote tumorigenesis. On aging, mammary glands of heterozygous MMTV-hBAG3 displayed densely crowded acinar structures with atypia, consistent with hyperplastic alveolar nodule (HAN). We subjected MMTV-hBAG3 mice to either multiparity or chemical carcinogenesis. After two pregnancies, most MMTV-hBAG3 animals had hyperplastic mammary ductal lesions (MMTV-hBAG3 6/7, 86%; FVB/N 1/7, 14%). Eighteen weeks post 7,12-dimethylbenz(a)antracene (DMBA) treatment, virgin females from five different transgenic lines had more hyperplastic lesions (MMTV-hBAG3 mean 6.3 lesions/gland, N=13, FVB/N mean 3.6 lesions/gland, N=9; p = 0.04), some with atypical hyperplasia. Transgenic MMTV-hBAG3 females developed ER and PR (+) malignant tumors (5/19), 26% while non-transgenic controls had none (0/12). WAP-Int3 mice developed tumors as early as two pregnancies. Heterozygous WAP-Int3xMMTV-BAG3 had the same tumor frequency but preliminary data suggest increased aggressiveness and metastasis. Collectively, our results indicate that MMTV-hBAG3 promotes proliferation, dysregulates mammary gland development and promotes hyperplasia and tumorigenesis and may provide a novel mouse model to represent the human ER+ luminal breast cancer subtype.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-04-08.
Abstract P2-05-15: Assessment of Notch Signaling Pathway Components as Biomarkers for Triple Negative Breast Cancer: Comparison of Triple Negative Breast Cancer Cell Lines and Human Breast Cancer Samples.
Authors: Zlobin A , Olsauskas-Kuprys R , Hodge S , O'Toole M , Ersahin C , Osipo C 
Published: August 2014

Abstract
Background: Treatment options for patients presenting with TNBC are limited, primarily because there is no approved targeted therapy available. Canonical breast cancer targets such as estrogen receptor and HER2/neu proteins are absent in TNBC. Furthermore, there is an urgent need to uncover biomarkers in this disease in light of its costly treatment as compared to non-TNBC treatment and, more importantly, its poor prognosis as evidenced by aggressive tumor metastasis and high patient mortality. While Notch-1 target gene expression has been reported to be linked to various types of malignancies, we propose that since Notch signaling pathway is involved in cancer cell proliferation and survival it could be a likely oncogenic driver and possible target in certain TNBC patients.
Methods: Human TNBC cell lines BT-549, MDA-MB-231, and MDA-MB-468 were used to measure endogenous relative mRNA transcript levels of Notch genes and gene targets by means of real time PCR. In addition, the RNA from formalin-fixed, paraffin-embedded specimen from women-diagnosed with TNBC who had undergone breast surgery was also analyzed for comparable gene expression for similar targets following Laser capture micro-dissection.
Results: The in vitro results show that mRNA transcripts of Notch-4, Deltex-1, Hes-1 and -Hes5, as well as upstream Notch regulator PEA3 targets IL-8 and MMP-9 were increased in MDA-MB-468 and BT-549 cells as compared to MDA-MB-231 cells (n = 3–5). In the clinical sample specimens, Notch-1, Jagged-1, and Hes-5 genes were up-regulated, while the Notch-4 gene was down-regulated in TNBC patients as compared to normal control specimens from reduction mammoplasty (n = 4).
Conclusions: Our data present the heterogeneity of TNBC disease. They also indicate that the Notch signaling pathway is up-regulated in certain TNBC cell lines and human TNBC breast cancer tissue. Lastly, these results suggest that some components of Notch signaling may be viable biomarkers to better predict Notch activity for future therapeutic interventions using Notch inhibitors.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-15.
Abstract P2-05-20: Validation and comparison of CS-IHC4 score with a nomogram based on Ki67 index, Adjuvant! Online, and St. Gallen risk stratification to predict recurrence in early Hormone Receptor (HR)-positive breast cancers
Authors: Park YH , Im S-A , Cho EY , Ahn JH , Woo SY , Kim S , Keam B , Lee JE , Han W , Nam SJ , Park IA , Noh D-Y , Yang JH , Ahn JS , Im Y-H 
Published: August 2014

Abstract
Background: Recently, the information in the IHC score was reported to be similar to that in the 21-gene Genomic Health recurrence score (GHI-RS). The aim of this study is to develop a nomogram based on Ki67 index to predict recurrence and to validate the nomogram by comparison with CS-IHC4 as well as Adjuvant! Online and St. Galen risk stratification. In addition, we validated our nomogram with external cohort.
Methods: We retrospectively analyzed the clinicopathologic characteristics and outcomes of 1,070 postoperative HR-positive breast cancer patients between 2004 and 2007 at the Samsung Medical Center to determine recurrence-free survival (RFS). We constructed nomogram using Cox proportional hazard model and validated externally in a cohort of 1,028 at Seoul National University Hospital. A prognostic model that used classical variables, Adjuvant! Online, St. Gallen risk stratification, and the four IHC markers (IHC4 score) were created and assessed in our cohort by LR-χ2 test using the bootstrapping method.
Results: Nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.70 (95% CI, 0.62–0.75) in the training set. The validation set showed a good discrimination with an AUC of 0.65 (95% CI, 0.58–0.72). In LR-χ2 test, the nomogram score was found to be more informative than the IHC4 with CS (LR-χ2 4.0539 [df1], 95% CI; 0.1038–8.004 for CS-IHC4 + nomogram score vs. CS-IHC4).

Prognostic significance was more prominent in N1 diseases than in the others (LR-χ2 4.199, 95% CI; 1.496–6.902 for CS-IHC4 + nomogram score vs. CS-IHC4).

However, Adjuvant! Online and St. Galen risk stratification did not show any definitive additional prognostic value.
Conclusions: We developed and validated a nomogram based on Ki67 index in external patients' cohort. It was compared with CS-IHC4 in our patients' cohort in early HR-positive breast cancers. This study implicates the amount of prognostic information contained in the nomogram is superior to that in the CS-IHC4 score.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-20.
Abstract P2-06-06: Integrating multiple molecular profiles with pathways to learn sub-type specific interactions with PARADIGM
Authors: Sedgewick AJ , Vaske CJ , Benz SC 
Published: August 2014

Abstract
High-dimensional omics profiling provides a detailed molecular view of individual breast cancers. We extended the Paradigm algorithm, a pathway analysis method for combining multiple omics data types with curated interactions on 7132 genes, to learn the strength and direction of curated interactions. Using only a single dataset, the 568 samples from the TCGA breast cancer cohort, we found strong high-throughput support for the majority of curated interactions. Gene set enrichment found that targets of the strongest interactions were significantly enriched for apoptosis and cell morphogenesis, and that strong regulators were significantly associated with phosphorylation. Within the TCGA breast cancer cohort the interactions some of the strongest support centered around ER alpha, IL23, GREB1, AKT1, and p53. We also assessed different strength between breast cancer subtypes, and found interactions associated with the MYC pathway and the ER alpha network to be among the most differential between basal and luminal A subtypes. Finally, we extended the method to assess the contextual dependence of interactions and found significant correlation between FOXM1 and JUN in regulation of CDK1.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-06-06.
Abstract P2-08-02: The large scale structure of the HER-2/neu amplicon in breast cancer
Authors: Pauletti G , Anderson L , Rong H-M , Yu J , Slamon DJ 
Published: August 2014

Abstract
Classical models of gene amplification envision chromosomally localized focal amplicons encompassing the immediate contiguous chromosomal regions flanking the driver gene. We present evidence that this is not the case for the HER2/neu amplicon in human breast cancer. Using a large panel of HER-2/neu positive cell lines, we observed that the HER-2/neu amplicon is made up of DNA segments mapping at different positions along chromosome 17. Sub-regions were subsequently re-amplified with the creation of condensed array of shorter amplicons. In addition, we show involvement of other chromosomes. The massive inter and intra-chromosomal reshuffling associated with amplified HER-2/neu containing sequences not only shed new light on the mechanism of gene amplification in human cancer but also have significant clinical implications for developing new targeted therapies and for combating drug resistance in this important subtype of breast cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-08-02.