bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-11-01: Intermittent High Dose Proton Pump Inhibitor Improves Progression Free Survival as Compared to Standard Chemotherapy in the First Line Treatment of Patients with Metastatic Breast Cancer
Authors: Hu X , Wang B , Sun S , Chiesi A , Wang J , Zhang J , Fais S 
Published: August 2014

Abstract
Purpose: High dose proton pump inhibitor (PPI) has proved to be potentially effective when combined with chemotherapy in preclinical data. This study (NCT01069081) was designed to investigate whether the efficacy of chemotherapy could be improved with the addition of proton pump inhibitor (PPI) in patients with metastatic breast cancer.
Patients and Methods: Females elder than 18 years old with histologically confirmed metastatic breast cancer were eligible for participation. Patients enrolled were randomly assigned to three arms: Arm A, docetaxol 75 mg/m2 on d4, followed by cisplatin 75 mg/m2 on d4, repeated every 21 days until maxinum 6 cycles or presence of disease progression or intolerable toxicity; Arm B, the same chemotherapy plus esomeprazole 80 mg p.o. bid three days on and the subsequent four days off, beginning on d1 repeated weekly up to disease progression, intolerable toxicity, patient's withdrawal, or a maximum of 66 weeks; Arm C, the same as Arm B with the only difference being dose of esomeprazole at 100 mg p.o. bid. The primary endpoint was progression free survival (PFS), and the secondary endpoints were time to progression (TTP), objective response rate (ORR), safety profile, and overall survival (OS).
Results: From Aug. 2009 to Dec. 2011, 100 women signed informed consent form (ICF) and 94 patients have undergone at least one injection of chemotherapy. Three patients had severe hypersensitivity reactions, two occurring after the first injection of docetaxol and one in the second cycle. After a median follow up of 17 months, 68 (72.3%) patients got disease progression and 23 (24.5%) patients died. Median PFS for the whole group (n = 94), arm A (n = 33), arm B (n = 30), arm C (n = 31) were 8.9, 7.5, 10.9, and 9.5 months, respectively (p = 0.082). A significant difference was observed between patients who had taken PPI and who not with median PFS of 9.5 and 7.5 months, respectively (p = 0.030). Among 17 patients with triple negative breast cancer, this difference was bigger with median PFS of 9.5 and 3.3 months, respectively (p = 0.014). The overall response rates for the whole group, arm A, arm B, arm C were 58.5%, 51.5%, 63.3%, 61.3%, respectively.
Conclusion: This trial is the first randomized study to demonstrate antitumor effects of intermittent high dose PPI in patients with metastatic breast cancer. Docetaxel and cisplatin doublet is comparable to the other first-line chemotherapeutical regimens and the addition of proton pump inhibitor to the doublet improves efficacy with no adding toxicity, especially in patients with triple negative breast cancer.
Key Words Proton Pump Inhibitor (PPI), Triple Negative Breast Cancer (TNBC), Phase II Study, Metastatic Breast Cancer, Chemotherapy
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-01.
Abstract P6-11-07: The Cancer Stem Cell-Targeting Wnt Inhibitor VS-507 Reduces Breast Cancer Growth and Metastasis
Authors: Ring JE , Kolev VN , Padval MV , Keegan M , Vidal CM , Neill AA , Shapiro IM , Pachter JA , Xu Q 
Published: August 2014

Abstract
Cancer stem cells (CSCs) support tumor viability and growth through their ability to self-renew and differentiate into heterogeneous tumor tissue. CSCs are typically resistant to standard cytotoxic agents, leading to their enrichment and the consequent regrowth of refractory tumors. While this population has been challenging to directly target therapeutically, we are actively developing novel agents, such as VS-507, that selectively target the cancer stem cell subpopulation in vivo.
Previously, we and others have shown that VS-507, a cancer stem-cell specific agent, inhibits Wnt signaling with corresponding reduction of the LRP6 protein, a Frizzled co-receptor upregulated in breast cancer cell lines. In the current study, we have continued to examine the effect of VS-507 on the Wnt/Beta-catenin signaling pathway to further elucidate its mechanism of action. We determined that VS-507 also decreases expression of the second Frizzled co-receptor LRP5 in MDA-MB-231 breast cancer cells stimulated by Wnt3A. The combined inhibition of the co-receptors LRP5 and LRP6 may contribute to the observed inhibition of Beta-catenin-mediated transcription by VS-507 in a TOP-Flash assay. Accordingly, VS-507 reduced expression of Axin2, a transcriptional target of Beta-catenin.
Because human breast cancer cell lines represent a mixed population of CSC and non-CSC cells, we evaluated VS-507 across a panel of cell lines by monitoring changes in viability and in the percentage of cancer stem cells. In SUM159 triple negative breast cancer cells, VS-507 had micromolar potency against the bulk population with preferential nanomolar potency against the ALDEFLUOR+ CSC population with similar effects observed in the Hoechst side population (SP) CSC assay. In contrast, cytotoxic anticancer drugs such as paclitaxel and cisplatin increased the percentage of ALDEFLUOR+ cancer stem cells under similar conditions. In vivo, oral administration of VS-507 (15 mg/kg, QD daily) as a single agent partially inhibited MDA-MB-231 tumor growth, consistent with its observed inhibition of the cancer stem cell subpopulation. Furthermore, VS-507 inhibited lung metastasis in a 4T1.2 murine breast cancer model. In summary, these results further elucidate the mechanism by which VS-507 inhibits Wnt/Beta-catenin signaling. VS-507 reduces tumor cell proliferation in vitro with preferential effects on cancer stem cells which translate to inhibition of tumor growth, enhancement of efficacy of cytotoxic agents such as docetaxel, and inhibition of metastasis in mouse models. These data provide additional support for the development of VS-507 as a novel anti-cancer stem cell agent.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-07.
Abstract P6-11-13: In vitro antineoplastic evaluation of rationally designed naphtoquinone-derived drugs in triple-negative breast cancer cell line
Authors: Madeira KP , Daltoé RD , Herlinger AL , Guimarães IS , Allochio Filho JF , Teixeira SF , Valadão IC , Greco S , Rangel LBA 
Published: August 2014

Abstract
Background: Breast cancer (BC) comprises multiple diseases harboring different genetic alterations, which subtypes respond differently to treatment, and are associated to distinct clinical outcomes. Likewise, triple negative breast cancer (TNBCs) are a heterogeneous subgroup of BC, immunophenotypically negative for estrogen and progesterone receptor, and HER2, that account for 10–15% of all invasive BC, affecting mostly African-American and Hispanic pre-menopausal women. Considering that TNBC have poor prognosis, and cannot be effectively treated with current targeted therapies, the discovery of new treatment options is imperative.
Methods: Novel naphtoquinone-derived drugs were rationally designed to act through multiple pathways aiming the avoidance of drug-resistant phenotype acquisition by tumor cells, and were synthesized following high efficiency and low cost method. Drugs antineoplastic efficacy (AE) was accessed in claudin-low TNBC cell line, MDA-MB-231, through the evaluation of cellular metabolic viability (CMV) (MTT method). Drugs structures are protected by patent. Cells were cultured in RPMI media supplemented with 10% (v/v) FBS and antibiotics until subconfluence; then, 1.5×105 cells/well were subcultured for 72h prior to treatment with drugs (10−4, 10−5, 10−6, 10−7, and 10−8 M). After 24h, CMV was assessed. Experiments in which the lineage was treated with cisplatin, doxorubicin or paclitaxel were run in parallel. The mean and standard-deviation of the absorbancies were used to calculate CMV and drugs IC50 (PrismaGraphPad version 5.1).
Findings: We screened the AE of 43 novel naftoquinones-derived drugs in MDA-MB-231 lineage; seven have decreased its CMV by, at least, 50%, as: PIC1 (IC50 1.15×10−4M; CMV decrease of 50%); PIC6 (IC50 4.24×10−5M; CMV decrease of 70%); PIC10 (IC50 5.07×10−5M; CMV decrease of 70%); PIC 20 (IC50 1.38×10−5M; CMV decrease of 90%); PIC21 (IC50 5.00×10−5M; CMV decrease of 70%); S5 (IC50 7.26×10−5M; CMV decrease of 60%); M20 (IC50 7.94×10−5M; CMV decrease of 60%). Their AE was significantly higher than that of cisplatin (IC50 1.56×10−4M; CMV decrease &lt; 10%), doxorubicin (IC50 1.76×10−4M; CMV decrease of 38%), and paclitaxel (IC50 5.05×10−7M; CMV decrease of 20%).
Interpretation: Altogether, our results present potential novel antineoplastic drugs to treat TNBC from a panel of in house rationally designed naftoquinones-derived compounds, developing an innovative and economically viable project.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-13.
Abstract PD03-01: EFFECT OF METFORMIN ON APOPTOSIS IN A PRESURGICAL TRIAL IN NON-DIABETIC PATIENTS WITH BREAST CANCER
Authors: Cazzaniga M , DeCensi A , Pruneri G , Puntoni M , Guerrieri-Gonzaga A , Dell'Orto P , Gentilini OD , Vingiani A , Pagani G , Puccio A , Bonanni B 
Published: August 2014

Abstract
BACKGROUND: metformin has been associated with antitumor activity in epidemiological and clinical studies. This effect has been related to different mechanisms of actions, including a reduction of the proliferative activity and an increase of apoptosis. We have recently shown that a 4 week pre-surgical treatment with metformin did not affect Ki-67 LI overall but reduced tumor proliferation Ki67 LI in breast cancer (BC) patients with insulin resistance (IR) (HOMA, fasting blood glucose (mmol/L)*insulin (mU/L)/22.5&gt;2.8) or BMI&gt;27 (Bonanni et al. JCO epub May 7, 2012). The objective of the current analysis was to determine whether metformin induced a modulation of apoptosis (TUNEL) overall and by HOMA index.
TRIAL DESIGN: After tumor biopsy we randomly allocated 200 non-diabetic women with operable breast cancer to either metformin (850 mg/bid) or placebo for 4 weeks prior to surgery. The primary outcome measure was the difference between arms in Ki-67 after 4 weeks of treatment. Here we analyzed the apoptotic cell nuclei in 88 consecutive core biopsies and their paired surgical samples from the initial 100 randomized subjects.
RESULTS: Median TUNEL levels at surgery (Metformin = 10%, IQR, 4–20, Placebo = 8%, IQR, 3–15) were significantly higher as compared with baseline (Metformin = 4%, IQR, 2–7, Placebo = 3%, IQR, 2–6, p &lt; 0.0001), but no difference between arms was noted (p = 0.2, adjusted for age, BMI, TUNEL and Ki67 at baseline). Interestingly, Ki67 and TUNEL levels were highly and positively correlated both at baseline and at surgery (Spearman r=0.51, p &lt; 0.0001). Furthermore, we found a trend to a different metformin effect by the HOMA index (p = 0.1). In the 59 women with HOMA &lt;2.8 there was a higher level of TUNEL at surgery on metformin versus placebo (p = 0.05), while an opposite trend was found in the 28 women with HOMA&gt;2.8 (p = 0.6).
CONCLUSIONS: The levels of TUNEL are significantly higher in the surgical specimens compared with baseline biopsy and are directly correlated with those of Ki-67 (TUNEL is high when Ki-67 is high). We found no significant modulation of TUNEL by metformin but a trend to a different effect according to the IR state, with a similar pattern to Ki-67: decrease by metformin in IR women and increase in non-IR women. Our findings confirm the notion that metformin has dual effects on breast cancer according to IR state. As expected, cancer apoptosis and proliferation are directly related. Our results strengthen the importance of placebo control arms in biomarker trials.
ACKNOWLEDGEMENTS: 2 Grants by AIRC and Italian Ministry of Health.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-01.
Abstract PD05-04: Targeted resequencing in oncogenetics: developing a new approach for molecular diagnostics
Authors: Sevenet N , Lafon D , Dupiot-Chiron J , Hubert C , Jones N , Debled M , de Lara Tunon C , Longy M , Bonnet F 
Published: August 2014

Abstract
Introduction: Next-generation sequencing (NGS) appears to be an accurate tool adapted for molecular oncogenetics. In contrast to certain somatic mutations, a lack of germline mutation hotspots in genes involved in cancer predisposition syndromes, especially hereditary breast and ovarian cancer (HBOC), force the molecular biologist to screen the entire coding sequence.
Material & methods: In order to screen a panel of genes predominantly involved in HBOC & Cowden disease in a molecular diagnostic setting, we captured 408 exons (and their surrounding intronic sequences) of 25 genes using the SureSelect oligonucleotide library capture (Agilent technologies). The bioinformatics resources Earray (Agilent technologies), Ensembl human genome v62 and UCSC repeat masker were used to create the capture design. This gave us 2899 unique 120-mers oligonucleotide probes which were duplicated 19 to 38 times depending on the GC content or the size of the targeted regions. Germline DNA of 190 patients (40 with previously identified mutations and 150 without previous molecular genetic analysis) was sequenced using a MiSeq bench top next-generation sequencer (Illumina) and in parallel was analyzed using our current screening method (EMMA, Enhanced Mismatch Mutation Analysis, similar to high resolution melting). Samples were prepared according the manufacturer's recommendations (Agilent technologies).
Results: All previously identified mutations along with 33 mutations in previously unscreened patients were detected. In addition, more than five hundred variants described as polymorphisms were identified. NGS seems to be more sensitive than our current screening method due to its detection and identification of homozygous variants. In order to limit the interpretation time, we restricted sequence analysis to the exon, −50 bp (including the acceptor splice site of the upstream intron) and +50 bp (including the donor splice site of the downstream intron). We have validated NGS as a technique adapted for germline mutation screening in oncogenetics. From the beginning of 2013, all germline DNA samples will be screened by NGS for oncogenetic molecular diagnostics. Sample preparation, technical organization, bioinformatics workflow and comprehensive results will be presented.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD05-04.
Abstract PD06-01: Automated computational Ki67 scoring in the GeparTrio breast cancer study cohort
Authors: Klauschen F , Wienert S , Blohmer J-U , Mueller BM , Eiermann W , Gerber B , Tesch H , Hilfrich J , Huober J , Fehm T , Barinoff J , Jackisch C , Erbstoesser E , Loibl S , Denkert C , von Minckwitz G 
Published: August 2014

Abstract
Background: Scoring proliferation through Ki67-immunohistochemistry is an important component in predicting therapy response to chemotherapy in breast cancer patients. Therefore, an accurate and standardized Ki67-scoring is pivotal both in routine diagnostics and larger multi-center studies aiming at improving present or establishing new cut-off values for existing or novel therapy regimens. However, recent studies have cast some doubt on the reliability of “visual” Ki67 scoring by pathologists, especially within the lower - yet clinically important - proliferation range. Here, we present and apply a novel automated image analysis approach for Ki67-quantification in breast cancer tissue.
Methods: We perform automated Ki67-scoring in 1219 breast cancer patients from the GeparTrio study cohort using a novel image analysis approach that avoids detection biases due to morphological variability by using a generic minimum-model approach. The method is capable of tumor-stroma-separation and may be used to process large data sets fully unsupervised in batch mode while allowing for efficient visual checks of the results. We compare these results with a different in-house-developed subtiling-based automated quantification method and moreover, gauge our approach with manual scoring performed by pathologists.
Results: The results show deviations of 10% (automated method 1 vs. manual), 9% (automated method 2 vs. manual) and 3% (automated method 1 vs. automated method 2) on average. The Ki67 scores show Pearson correlations between automated and manual scoring of r&gt;0.8 (p &lt; 0.001) for both automated methods and r&gt;0.95 (p &lt; 0.001) between the two tested automated methods.
Conclusion: Because of the methodological differences of the presented techniques our results suggest a high robustness of the automated methods that at the same time show a good agreement with manual Ki67 scoring. Our approach therefore offers an automated and standardized means of Ki67 quantification applicable in routine diagnostics as well as larger clinical study settings, such as in the GeparTrio cohort shown here.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD06-01.
Abstract PD06-05: St. Gallen 2011 clinico-pathological subtypes of breast cancer: concordance of core biopsies and related surgical specimens
Authors: Decker T , Focke CM 
Published: August 2014

Abstract
Rationale: Whereas the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011 considered molecular typing as the adequate model representing the heterogeneity of breast cancers, it did not generally accept gene expression array criteria for clinical decision making. When the classification of tumours by gene expression array criteria and immunohistochemical analysis of ER, PR and HER2 are discrepant, patients should be managed according to the current immunohistochemical markers. Therefore, for systemic therapy decision the St Gallen consensus Conference 2011 did recommend clinicopathologically defined breast cancer subtypes (cpBCST) to guide therapeutic choices. There are many reasons to provide patients and doctors these information already preoperatively. To evaluate relevance of St. Gallen 2011 cpBCST core biopsy (CB) results we estimated their concordance with postoperative cpBCSTs.
Methods: cpBCSTs of CB and related surgical specimen (SSP) of 379breast cancers (BC) (62 Grade 1, 157Grade 2, 160 grade 3) were assessed according to the St Gallen definition using the prospectively estimated results for Estrogen, Progesteron, and Her2-status. To differentiate between Luminal A and the Her2 negative subgroup of Luminal B we retrospectively measured the mitotic activity index (MAI) with a cut-off of ≥10 for high versus low as evaluated by Baak et al. 2008. Concordance between cpBCST results of CB and SSP and PPV of cpBCST of CB were calculated.
Results:

None of the Luminal A BCs was overestimated in CB, whereas 49% (53/108) of all Luminal B or 66% (55/83) of the Luminal B (Her2−) BCs were underestimated as Luminal A, for all other subtypes, the agreement was 100%. In general, there was no overestimation as a more unfavourable CPBCST in CB. The overall underestimation rate came out with 14%. Whereas the PPV in CB is 100% for Luminal B, Her2 positive, and Triple negative CPBCSTs, it is only 78% for Luminal A (198/254). The reason is underestimation of proliferation in CB.
Conclusions: BC subtypes classified according to the St. Gallen clinicopathological definitions on CB show a high agreement with corresponding SSP results. The respective PPVs are also generally high. This means that clinicopathological subtyping on CB can be used for preoperative decision making in the vast majority of cases. However, for the Her2 negative subgroup of Luminal B subtype in CB the agreement with SSP is lower due to underestimation of proliferation in CB.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD06-05.
Abstract PD06-08: Strong prognostic concordance between Ki67 and binary, but not multi-level gene expression signatures
Authors: Tobin NP , Lindström LS , Carlson JW , Bergh J , Wennmalm K 
Published: August 2014

Abstract
Background: Several proliferation-related gene signatures have been proposed to aid breast cancer management by providing better prognostic and therapy predictive information on a patient-by-patient basis. It is unclear however, whether a less demanding assessment of cell division rate (as determined by Ki67 expression) can function in place of gene profiling.
Methods: Agreement between literature-, distribution-based, as well as signature-derived threshold values for Ki67, relative to the genomic grade index (GGI), the 70-gene signature, the p53 signature, the recurrence score (RS), and the molecular subtype models of Sorlie, Hu, and Parker was investigated in a representative set of 253 breast cancers with 25 years follow up. Relevance for breast cancer specific survival was assessed for contrast groups, and in uni- and multivariate Cox models.
Results: Our broad approach identified Ki67 cutoffs in the range of 10%–20%. With optimum signature-reproducing cutoffs, similarity in classification of individual tumors was high for GGI (81%), the 70-gene (78%), and the p53 (82%) signatures, but lower for the recurrence score (68%), Sorlie (68%), Parker (67%) and Hu (68%) signatures. Consistent with strong agreement, no prognostic superiority was noted for Ki67 vs. the binary GGI, 70-gene and p53 signatures respectively, in multivariate analyses. In contrast, Ki67-independent prognostic capacity could be demonstrated for RS and molecular subtypes according to Sorlie, Parker and Hu (Table 1).
Conclusions: The added prognostic value of binary proliferation-related gene signatures appears limited for Ki67-assessed breast cancers. More complex, multi-level descriptions seem to have a greater potential in pinpointing the outcome heterogeneity in breast cancer. We aim to validate our findings in a second cohort of 159 breast cancer patients with over 15 years of clinical follow up.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD06-08.