bluuebunny/crossref_metadata_2025_split huggingface dataset:
Three-Year Follow-Up of Survival and Progression in a Phase II Trial of Gemcitabine Plus Carboplatin (Plus Trastuzumab in HER2+ Patients) in Metastatic Breast Cancer Patients.
Authors: Loesch D. , Loesch D. , Asmar L. , McIntyre K. , McIntyre K. , Orlando M. , Zhan F. , Boehm K. , O'Shaughnessy J. , O'Shaughnessy J. , O'Shaughnessy J. 
Published: December 2010

Abstract
Background: We have previously reported (Loesch, et al. Clin Breast Cancer, 2008) the efficacy and safety of gemcitabine and carboplatin with or without trastuzumab in patients with metastatic breast cancer. We now report time-to-progression (TTP) and overall survival (OS) after up to 3.5 years of extended follow-up.Patients and Methods: Patients were stratified into 3 groups at registration; Group 1: HER2 positive (+) regardless of prior taxane; Group 2: HER2 negative (–) and taxane naïve or remote (no taxanes within the past 2 years); and Group 3: HER2– and taxane pretreated. Women ≥18 years of age, with ECOG performance status 0-2, with RECIST-defined measurable disease, and either HER2– or HER2+ (3+ score) by immunohistochemistry or fluorescence in situ hybridization were enrolled. Treatment: Day 1 gemcitabine 1500 mg/m2 over 30 minutes followed by carboplatin AUC=2.5 repeated every 14 days up to Cycle 9. Group 1 also received trastuzumab 8 mg/kg in Cycle 1 followed by 4 mg/kg in Cycles 2-9, followed thereafter by 6 mg/kg every 21 days until progression or intolerable toxicity.Results: A total of 150 patients were registered (50, 51, and 49 in Groups 1, 2, and 3, respectively). Median follow-up for surviving patients, calculated from registration, was 31.3, 27.1, and 25.4 months, respectively. Median TTP (calculated as progression-free survival), was 7.2, 5.6, and 4.6 months, respectively. Median OS (range) has not been reached for Group 1 (range, 1.2-46.9); for Group 2 was 21.7 months (&lt;1-44.3); and, for Group 3 was 11.9 months (&lt;1-33.6). At 24-months, survival rates were 73.3%, 41.4%, and 20.5%, respectively; at 36-months, survival rates were 60.6%, 25.7%, and ≤8.3%, respectively. For Group 1 only, the remaining 3 responding patients were followed for 3.5 years, at which time they were relapse-free.Conclusions: Gemcitabine plus carboplatin with or without trastuzumab has been shown to be highly active in metastatic breast cancer. HER2+ patients receiving trastuzumab had the highest TTP and survival rates of all treatment groups. As expected, taxane-pretreated patients had shortened TTP and decreased OS rates compared to taxane-naïve patients.Research support was provided, in part, by Lilly USA, LLC; Indianapolis, IN.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2105.
Subgroup Analyses in Contemporary Phase III Trials in Advanced Breast Cancer (ABC).
Authors: Calabrich A. , Katz A. , Saad E. 
Published: December 2010

Abstract
Objective: Subgroup analyses of treatment effects according to baseline patient characteristics are often performed in phase III trials in oncology. However, the frequency and determinants of this practice in ABC have not been described in the literature.Methods: We used the medical subject headings “breast neoplasms” and “drug therapy” to search PubMed for phase III trials on systemic antineoplastic therapies published between 01/00 and 12/07 in one of 10 leading medical journals (Ann Oncol, BCRT, Br J Cancer, Cancer, Eur J Cancer, JCO, JNCI, Lancet Oncol, Lancet and NEJM). We excluded factorial trials and studies on high-dose chemotherapy. When a subgroup analysis was not reported in the main article for each trial, a PubMed search was conducted using the names of first and last authors (separately) and the experimental drug(s). All variables were analyzed as reported by the authors of trials.Results: The initial search yielded 58 trials enrolling a total of 23,371 patients in 122 trial arms. For 31 trials (53.4%), a subgroup analysis was reported in the main article. Another 7 trials reported a subgroup analysis in a companion paper, for a total of 38 out of 58 trials reporting a subgroup analysis (65.5%; 95% CI, 51.8 – 77.2%). Such analyses were reportedly pre-planned in only 11/38 cases (28.9%), and only two trials reported a formal test for interaction. The number of factors considered in subgroup analyses ranged from 1 to 14. In 21/38 cases (55.3%), none of these factors was used for stratification before randomization. The results of the subgroup analysis were mentioned in the main article abstract in 13/31 cases (41.9%), 5 of which in the conclusions. There was no difference in the proportion of positive (70.4%) and negative (61.3%) trials (regarding their primary endpoints) for which a subgroup analysis was reported (P=0.53). Likewise, financial support (pharmaceutical industry [N=36] vs others [N=22]) was not predictive of subgroup analysis (P=0.17). However, trials published between 2000 and 2003 were more likely (P=0.03) to report a subgroup analysis (79.3%) than trials published between 2004 and 2007 (51.7%).Conclusion: Our review suggests that subgroup analyses are frequently performed in phase III trials in ABC. In the vast majority of cases, no formal test for interaction is presented. There seems to be a temporal trend for decrease in reporting of subgroup analyses. Other potential predictors of subgroup analysis are currently being sought.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2107.
Prognostic Significance of Molecular Subtypes in Male Breast Cancer.
Authors: Foerster R. , Foerster F. , Foerster F. , Wulff V. , Schubotz B. , Lange R. , Habeck J. , Baaske D. , Baaske D. , Kuhn W. , Rudlowski C. 
Published: December 2010

Abstract
INTRODUCTIONThe relatively unfavorable outcome in male breast cancer has been attributed to more advanced local tumor stage and high incidence of lymph node invasion at the time of diagnosis. This study aimed to classify the molecular subtypes of male breast cancers based on the expression profile of immunomarkers and to evaluate their association with clinicopathological features and patients outcome.METHODSTo define molecular subtypes a total of 174 cases of male breast carcinoma were examined retrospectively using immunostains for hormone receptors (HR) and cytokeratin 5/6 (CK5/6). Human epidermal growth factor receptor 2 (HER2) expression was evaluated by immunostaining and confirmed by fluorescent in situ hybridization. Tumor characteristics and overall survival (OS) data were available and correlated with protein expression and the molecular subtype.RESULTSThe luminal A subtype (HR+/HER2-) was the most common subtype in male breast cancer (82.8%; n=144) with a median patients OS of 122 month. Luminal B tumors (HR-/HER+) were found in 6.2% (n=11), basal-like (HR-/HER2-/CK5/6+) in 9.6% (n=17) and HER2+/HR- carcinomas in 1.1% (n=2). Basal like male breast carcinoma showed a statistically significant reduced overall survival (median: 51 month; p&lt;0.01). Due to the low number of patients prognostic significance of HER2 positivity (luminal B and HER2+/HR-subtype) was not evaluable.CONCLUSIONSIn our study group, luminal A was the predominant subtype of male breast carcinoma and showed an excellent patients outcome. However, like in females tumors with a basal like subtype which were known to show minor chemotherapy response had a worse prognostic outcome. Therefore, new therapeutic options have to be defined.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2110.
Single Nucleotide Polymorphisms of CYP19A1, rs10459592 and rs4775936 Predict Clinical Benefit of Letrozole in Patients with Metastatic Breast Cancer.
Authors: Park I. , Ro J. , Lee K. , Kim S. , Lee Y. 
Published: December 2010

Abstract
BackgroundThe CYP19A1 gene encodes the enzyme aromatase, which is involved in the production of estrogen in various tissues. We evaluated the efficacy of an aromatase inhibitor, letrozole in metastatic breast cancer patients according to DNA polymorphisms of the aromatase gene CYP19A1.Patients and methodsPatients (n=113) with hormone receptor positive metastatic breast cancer were treated with letrozole. Monthly GnRH agonist was added in premenopausal patients. DNA was isolated from peripheral blood samples and was genotyped for 50 polymorphisms of CYP19A1 by iPLEX Gold assay based on matrix-associated laser desorptional ionization, time-of-flight mass spectrometry.ResultsAmong 50 examined single nucleotide polymorphisms (SNP), 10 SNPs were revealed as monomorphic for Korean population. After trimming of the data using HWE test, rs10459592 (T/G) and rs4775936 (C/T), which were located in exon I.6 of CYP19A, were significantly associated in an over-dominant model with higher disease control rate (CR+PR+SD≥ 6months) (HR=2.82 [95% CI 1.21-6.59], p=0.0149; HR=2.62 [95% CI 1.12-6.10], p=0.0238, respectively). In linkage disequilibrium analysis, these were strongly linked (D'=1.0, r2=0.936), and subsequent haplotype analysis showed a statistical significance with regard to higher disease control rate (HR=2.61 [95% CI 1.12-6.1], p=0.0238). Median time to progression (TTP) with a median follow-up of 85.7 months (range 9.7-107.4 months) was improved in patients having over-dominant form of rs10459592 without statistical significance (median 7.74 months [95% CI 6.48-9.00] vs. median 12.07 months [95% CI 8.87-15.26], p=0.147). In multivariate analysis, rs10459592 (HR=2.81 [95% CI 1.12-7.06], p=0.027) was an independent factor affecting disease control rate besides age (HR=1.06 [95% CI 1.01-1.12], p=0.019) and HER2 positivity (HR=0.25 [95% CI 1.12-7.06], p=0.027).ConclusionIn patients with hormone responsive metastatic breast cancer treated with aromatase inhibitor, letrozole, the presence of SNPs in the exon I.6 of CYP19A1, rs10459592 and rs4775936 were significantly associated with improved treatment efficacy. Although further study is needed, our data present possible candidate markers for the letrozole treatment in metastatic breast cancer. (NCC grant number 0910320-1)
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2117.
Microtubule Associated Protein-Tau (MAPT) Is Influenced by ER: ICI182,780, a Selective ER Inhibitor, Down-Regulates MAPT Expression and Reverses Resistance to Taxanes in MAPT- and ER-Positive Breast Cancer Cells.
Authors: Ikeda H. , Taira N. , Hara F. , Nogami T. , Shien T. , Doihara H. 
Published: December 2010

Abstract
Background: Taxanes are important drugs in treatment of breast cancer. These drugs bind to tubulin and suppress spindle microtubule dynamics, which leads to cell cycle arrest in the G2/M phase followed by apoptosis. However, resistance to taxane therapy prevents some patients from benefiting from these drugs. Several mechanisms of taxane resistance have been described, including the involvement of microtubule-associated protein-tau (MAPT). MAPT binds to the same pocket as taxanes in microtubules and obstructs the function of the drug. Estrogen receptors (ER) are transcriptional factors that play an important role in the development and progression of breast cancer. However, the relationship between ER and MAPT in breast cancer is not entirely clear. In this study we examined the correlation between MAPT expression and the sensitivity of human breast cancer cells to taxanes, and the relationship between ER and MAPT at the protein level in these cells. We also examined combination therapy with hormone drugs and taxanes.Methods: The correlation between MAPT expression and sensitivity to taxanes was examined in 12 human breast cancer cell lines using real time PCR, western blotting analysis and an MTS assay. Following small interfering RNA (siRNA) knockdown of MAPT expression, the alteration of cellular sensitivity to taxanes was examined by MTS assay, flow cytometry and immunofluorescence. To examine the relationship between ER and MAPT, ER expression was knocked down with siRNA or stimulated with 17-β-estradiol in MAPT- and ER-positive cell lines (MCF-7 and ZR75.1, respectively). The cells were also treated with hormone drugs (tamoxifen and ICI182,780) and changes in MAPT protein expression were examined.Results: Six cell lines showed high MAPT mRNA expression and four showed high MAPT protein expression; that is, expression at the mRNA level did not always correlate with that at the protein level. MAPT mRNA expression did not correlate with taxane resistance, but expression of MAPT protein isoforms under 70 kDa correlated with taxane resistance. Downregulation of MAPT increased sensitivity to taxanes. MAPT protein expression was decreased by ER knockdown and increased by 17-β-estradiol stimulation. The MAPT protein level was also increased by tamoxifen, but decreased by ICI182,780. Combination treatment of taxanes with ICI182,780 showed a strong synergistic effect, but similar treatment with tamoxifen had an antagonistic effect in both cell lines.Conclusions: Expression of MAPT protein isoforms under 70 kDa correlates with taxane resistance in breast cancer cells. MAPT expression is influenced by ER in breast cancer and ICI182,780, a selective ER inhibitor, can reverse the resistance to taxanes in both MAPT- and ER-positive breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2118.
Aberrations of HER2 and TOP2A Genes in Breast Cancer.
Authors: Nielsen K. , Müller S. , Møller S. , Schønau A. , Balslev E. , Knoop A. , Ejlertsen B. 
Published: December 2010

Abstract
Copy number changes in TOP2A are frequently observed in HER2 amplified breast cancers, and amplification of a whole amplicon containing both genes has been suggested as the underling mechanism. Here, we describe copy number changes of HER2 and TOP2A in two cell lines; one characterized by having amplification of both genes and the other by having amplification of HER2 and deletion of TOP2A. The characteristics are compared to findings in patients with invasive breast cancer.Material and methods: Fluorescence in situ hybridization (FISH) with HER2, TOP2A and centromere 17 (CEN-17) probes was performed on metaphases, interphases and cut sections from breast cancer cell lines. Paired HER2/CEN-17 and TOP2A/CEN-17 data was available from 649 patients from a previously published biomarker study (Knoop et al. J Clin Oncol 2005;23:7483-90).Results: The physical localization of FISH signals in metaphase spreads from cell lines showed that simultaneous amplification is not a simple co-amplification of a whole amplicon containing both genes. HER2 and TOP2A aberrations seem to be due to different mechanisms of amplifications. Most gene signals are translocated to abnormal marker chromosomes. HER2 genes but not TOP2A genes are present in tandem amplicons, leading to a higher HER2 ratio. This observation was confirmed by patient FISH data: 373 tumors (57%) had normal status for both genes. Among the 276 abnormal tumors, 67% had different HER2 and TOP2A status. Simultaneous amplification of both genes was found in 28% of the abnormal tumors (12% of all patients) while deletion of both genes was observed in 5% of the cases (2% of all patients). The average gene/reference ratio was significantly different: 5.0 for TOP2A but 7.2 for HER2 in the amplified tumors (P&lt;0.001; χ2-test). In the HER2 assay 398 (61%) of the 649 tumors had more than 4 gene signals per nucleus while only 96 (15%) of the tumors had more than 4 TOP2A signals per nucleus.Conclusion: In the majority of breast cancer patients, simultaneous aberration of HER2 and TOP2A is not explained by simple co-amplification. Amplification of the two genes may be caused by different mechanisms, leading to higher level of amplification for HER2 compared to TOP2A.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2119.
Crosstalk between Estrogen Receptor alpha 36, a Dominant Extra-Nuclear ER, and HER2 Promotes Tumor Cell Survival in Breast Cancer.
Authors: Jiang L. , Huang J. 
Published: December 2010

Abstract
The ER-α36 protein is a 36kDa novel splice variant of the full length 66kDa ER-α. ER-α36 lacks both transcriptional activation domains of ER-α66 but retains the DNA-binding domain and partial dimerization and ligand-binding domains. It has been shown that ER-α36 could trigger membrane-initiated signaling in ER-α36 over-expressing 293 cells, suggesting that ER-α36 might have functions linked with activation of intracellular signaling.To further explore the mechanism(s) of ER-α36 activation of intracellular signaling, in particular the possible relationship between ER-α36 and HER2 in breast cancer, we performed a pilot study. First, we examined the correlation between ER-α36 and HER2 by immunohistochemistry (IHC) using a specific anti-ER-α36 antibody designed against a unique epitope located in the C-tail of ER-a36 which is not present in ER-α66. The results showed that the expression of ER-α36 was highly associated with HER2 in a cohort of 249 breast tumors (P&lt;0.05). Then, we examined whether ER-α36 physically interacts with HER2 in breast cancer cell lines using co-immunoprecipitation (Co-IP) and Western blotting (WB) experiments. We found that ER-α36 interacts with HER2 in both MCF7/HER2 and BT474 cell lines. Second, we explored whether ER-α36 influences the activation of HER2 and its downstream signaling by knocking down ER-α36 expression in both MCF7/HER2 and BT474 cell lines. We found that knockdown of ER-α36 by siRNA abrogated the activation of P-HER2, as well as Akt and MAPK, in both MCF7/HER2 and BT474 cells. Finally, we asked the key question whether ER-α36 was associated with cell proliferation/survival. Strikingly, we found that when both MCF7/HER2 and BT474 cells were deprived of ER-α36 by siRNA, they died quickly, whereas control cells grew normally.In conclusion, our preliminary data suggests that there might be a crosstalk between ER-α36 and HER2 signaling, and that this crosstalk might promote tumor cell survival through HER2/Akt and/or HER2/MAPK signaling pathways in breast cancer. Thus, ER-α36 may be a valuable biomarker and a novel therapeutic target in breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2121.
Development of a Novel GREB1 Monoclonal Antibody and Applications in Breast Cancer Research.
Authors: Hnatyszyn H. , Liu M. , Hilger A. , Thomas D. , Rae J. , Lippman M. 
Published: December 2010

Abstract
It has been well established that GREB1 mRNA expression is induced by estrogen in breast cancers and that GREB1 is critically involved in the estrogen-induced growth of breast cancer. To date, all studies of GREB1 have focused on mRNA levels using PCR and array technologies with very little known about GREB1 protein expression in normal and breast cancer cells. The lack of a specific antibody to GREB1 has inhibited protein-based investigations in target cells. Our collaborative research group has generated a novel monoclonal GREB1 antibody (GREB1ab) for research use in Western blotting as well as immunohistochemical (IHC) applications.Our team created a hybridoma expressing a murine monoclonal antibody against a 119 amino acid peptide specific to human GREB1. By Western Blot Analysis, GREB1ab detects a 216 kD protein corresponding to GREB1a in ER+ breast cancer cells expressing GREB1 as well as cells transfected with a GREB1a expression plasmid. GREB1ab specificity was verified using ICI 182,780, an estrogen receptor antagonist to prevent GREB1 induction, as well as silencing siRNA targeting GREB1 mRNA expression. GREB1 protein expression was reduced in MCF-7 cells treated with estrogen plus ICI 182,780 compared with that of estrogen treatment. There was no detectable GREB1 protein expression when GREB1 mRNA is silenced by siRNA at 48 hours. In a time course study, inhibition of GREB1 protein occurred as early as 24 hours and lasted up to 72 hours. Thus, by Western Blot Analysis, the monoclonal GREB1ab is specific for GREB1 and can be employed to detect changes in GREB1 expression in breast cancer cell lines under various experimental conditions.GREB1ab was validated for detection of GREB1 by IHC in breast cancer cell lines and breast tissue microarrays (TMA). IHC staining with GREB1ab revealed GREB1 was strongly expressed in the ERα-positive breast cancer cell line, MCF-7, with weak GREB1 expression in ERα-negative MDA-231 cells. A panel of breast cancer cell lines was screened for endogenous expression of GREB1 protein in a TMA format using IHC. As expected, ER-positive cell lines (n=5) were observed to express GREB1 while ER-negative cell lines (n=11) did not express detectable levels. Using breast cancer tissue whole sections, IHC with the GREB1ab indicated protein expression in ERα positive breast cancer tissue as well as normal breast tissue, with little GREB1 expression in ERα negative breast cancer tissue.The monoclonal GREB1ab is specific for GREB1 protein. This antibody will serve as a tool for investigations focused on the expression, distribution and function of GREB1 in normal breast and breast cancer tissues.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2126.
Discordant HER2 Total and HER2 Homodimer Levels by HERmark Analysis in Matched Primary and Metastatic Breast Cancer FFPE Specimens.
Authors: Leitzel K. , Conte P. , Guarneri V. , Barbieri E. , Huang W. , Ali S. , Ali S. , Haddad M. , Sperinde J. , Lie Y. , Weidler J. , Bates M. , Lipton A. 
Published: December 2010

Abstract
Background: HER-2/neu is over-expressed in approximately 25% of primary invasive breast cancers and selection of patients for consideration of trastuzumab is a critical step in defining the treatment plan. We have previously reported that quantitative measurements of HER2 protein expression (H2T) and HER2 homodimers (H2D) using the HERmark assay identifies sub-populations of “HER2-positive” patients (by IHC and/or FISH) that have different clinical outcomes on trastuzumab (Leitzel, ASCO 2008; Lipton, SABCS 2008). Previous studies report up to a 20 % discordance in HER2 status using conventional IHC or FISH analysis between the primary and metastatic breast tumors. Here we correlate HER2 total and homodimer levels in matched primary and metastatic tissue from the same patient.Methods: 27 patients had matched primary and metastatic FFPE (formalin-fixed, paraffin-embedded) specimens tested in the HERmark assay to quantitate and compare their H2T and H2D expression levels.Results: FFPE tissue was available from 27 primary breast cancers and metachronous metastatic sites. Metastatic lesions included 7 skin, 5 lymph node, 3 bone, 3 pleura, 2 brain, 2 chest wall, and 5 other soft tissue lesions. The median elapsed time between matched primary and metastatic sites was 71 mo. (range 9-137 mo). During the time period between the primary specimen harvest and the metastatic biopsy, 6 patients were treated with chemotherapy alone, 10 received hormonal therapy without trastuzumab, 3 patients received trastuzumab, and 3 received no treatment. Treatment was not known for 5 patients. For the whole population, there was a weak to moderate positive correlation between primary and metastatic cancers with H2T (r2=0.36, p&lt;0.001) and for H2D (r2=0.27, p&lt;0.006). Using the optimized time to progression (TTP) positional scanning cutpoints for H2T and H2D defined in our previous reports, 4/20 patients (20%) converted from low to high, and 1/7 (14%) converted from high to low H2T. Using the H2D cutpoint, 7/15 patients (47%) converted from low to high, and 3/12 (25%) converted from high to low H2D. Overall discordance between primary and metastatic sites was 19% for H2T, and 37% for H2D.Conclusions: HERmark analysis of matching primary and metastatic breast cancers revealed 19% discordance for H2T, and 37% for H2D. The most frequent conversion was from low HER2 in the primary tissue to high HER2 in the metastatic site.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2131.