bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Breast Cancer Stem Cells (CSCs) by Novel STAT3 Inhibitors.
Authors: Dave B. , Tweardy D. , Lewis M. , Chang J. 
Published: December 2010

Abstract
Background: Many patients with breast cancer relapse over time despite an initial response to systemic therapy. One explanation is that a rare sub-population of CSCs with tumorigenic potential is intrinsically resistant to therapy. Previously, we showed that residual tumors after chemotherapy are 1) enriched for the tumorigenic CD44+/CD24-/low population, 2) show enhanced mammosphere-forming efficiency (MSFE), and 3) display an increase in outgrowth potential in xenograft transplants in immunocompromised SCID/Beige mice. Gene expression profiling of CD44+/CD24-/low and mammosphere-forming cells derived from human breast cancer biopsies revealed that the top canonical pathways in CSC self-renewal included STAT3 signaling. We hypothesized that inhibition of STAT3 would lead to a decrease in the number of breast CSCs either alone, or in combination with systemic therapies. Methods: We established primary xenografts in immunocompromised SCID/Beige mice from biopsies of primary human breast cancers; that faithfully recapitulate biology similar to the primary breast cancers in patients. We tested two classes of drugs that target Stat3--G-quartet oligodeoxynucleotide (GQ-ODN, T40214) and small molecules (Cpd188 and its derivatives)--for their ability to inhibit human breast cancer xenograft MSFE.The GQ-ODN T40214 was previously shown to target the Stat3 Src homology (SH) 2 domain destabilizing Stat3 dimers while Cpd188 was identified using virtual ligand screening and was shown to competitively and selectively inhibit binding of the Stat3 SH2 domain to its phosphotyrosine (pY) peptide ligand. Cpd188 derivatives were identified by 2-D similarity screening using the scaffold of Cpd188 and 3-D pharmacophore analysis and their activity confirmed by pY peptide binding inhibition. A triple negative (ER-negative, PgR-negative, and HER-2) tumor line (n=3 mice/group) was treated with Cpd188 (125mcg or 250mcg), T40214 (125mcg or 250mcg), a control non-specific (NS) ODN (125 or 250 mcg) or vehicle alone. The animals were sacrificed after two days of treatment and MSFE determined. In addition, we tested the 39 Cpd188 derivatives for the ability to decrease MSFE in vitro. Results: In these short term experiments, a statistically significant reduction (p≤0.05) was observed in the MFSE with Cpd188 (250mcg) and T40214 (125 and 250 mcg) vs. control. Of the 39 Cpd188 derivatives, 11 derivatives significantly decreased MSFE in two triple negative cell lines (SUM159PT and HS578T). Conclusions: STAT3 inhibition using 2 classes of molecules that target its SH2 domain significantly reduced CSC in both in vivo and in vitro assays raising the possibility that breast cancer therapeutic regimens that contain agents that target Stat3 may reduce relapse rates.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1155.
Mammary Stem Cell-Like Gene Expression and Relation to Cancer.
Authors: Williams C. , Helguero L. , Edvardsson K. , Haldosén L. , Gustafsson J. 
Published: December 2010

Abstract
Mammary stem cells are bipotential and suggested to be the origin of breast cancer development, but are elusive and vaguely characterized.Breast tumors can be divided into subgroups, each one requiring specific treatment. To determine a possible association between mammary stem cells and breast cancer, we have previously made a detailed characterization of the transcriptome in murine mammary epithelial stem-like cell line (HC11) and made a thorough investigation of global gene-expression changes during stepwise differentiation using dual-color comparative microarray technique.Subsequently, we performed a cross-species comparison to reveal conserved gene expression between stem cells and subtype-specific and prognosis gene signatures, and correlated gene expression to in vivo mammary gland development. Our analysis provided a unique map of the transcriptomic changes and a number of novel mammary stem cell markers. Interestingly, our comparisons show that specific subtypes of breast cancers with poor prognosis and metastasizing capabilities show resemblance to stem-like gene expression. We are now investigating several marker candidates and regulations of miRNAs during differentiation.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1162.
Disease Related Outcome with Long Term Follow-Up: An Updated Analysis of the Intergroup Exemestane Study (IES).
Authors: Bliss J. , Kilburn L. , Coleman R. , Forbes J. , Coates A. , Jones S. , Jassem J. , Delozier T. , Andersen J. , Paridaens R. , Coombes R. 
Published: December 2010

Abstract
Background: IES is an investigator-led study in 4724 postmenopausal patients with early breast cancer (sponsored by Pfizer Ltd; ISRCTN11883920) that has already demonstrated significant, clinically important benefits from switching adjuvant endocrine therapy after 2-3 years tamoxifen (T) to exemestane (E) (NEJM 2004, Lancet 2007). With longer follow-up the sensitivity of a disease free survival analysis may be reduced by the increasing number of non breast cancer-related deaths. Analysis of breast cancer free survival (BCFS), censoring intercurrent deaths, provides a sensitive estimate of the true impact of an adjuvant intervention on breast cancer outcome.Materials and methods: Patients who were disease-free after 2-3 years of adjuvant T, were randomized to continue T or switch to E to complete a total of 5 years of adjuvant endocrine therapy. At the time of this planned analysis in June 2009, the median follow-up was 91 months, and 91% of surviving patients had ≥6 years followup. The analysis focuses on 4052 pts known to be ER positive (+) and 547 with ER unknown (unk) tumors. The remaining 125 patients now known to be ER negative are excluded from this analysis.Results: 933 BCFS events have been reported (E=425 T=508) giving an unadjusted hazard ratio (HR) of 0.81 (95%CI: 0.71, 0.92); p=0.001 in favor of E in the ER+ and ER unk groups. With mature follow-up, the benefits of E appear similar in the ER unk and ER+ sub-groups (HR=0.85 95%CI (0.60, 1.20); p=0.36 and HR=0.80 95%CI (0.70, 0.92); p=0.002 respectively). Similarly, all other prognostic subgroups show consistency with the overall BCFS effect. An analysis partitioned at 2.5 years post randomization showed the on-treatment BCFS benefit of switching to E (HR=0.60 95%CI (0.48, 0.75); p&lt;0.0001) was maintained post-treatment (HR=0.94 95%CI (0.80, 1.10); p=0.46). Continuing improvement in OS was demonstrated, with E=352 versus T=405 deaths (HR=0.86, 95%CI (0.75, 0.99); p=0.04). Of these, 219 were reported as intercurrent deaths (E=105, T=114).Conclusions: The protective effect of switching to E, compared with continuing on T, on relapse rate is maintained for at least 5 years post treatment completion. Associated with this is a continuing benefit on overall survival.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 12.
Lack of Correlation between Genetic Polymorphisms in Tamoxifen Metabolizing Enzymes with Primary Endpoints in the IMPACT Trial.
Authors: Rae J. , Thibert J. , Sikora M. , Johnson M. , Skene A. , A'Hern R. , Smith I. , Dowsett M. 
Published: December 2010

Abstract
Background. Several studies aimed at correlating genetic variants in the enzymes responsible for tamoxifen metabolism and disposition with therapeutic outcomes have provided equivocal and conflicting data. The IMPACT trial compared the preoperative used of tamoxifen with anastrozole alone or in combination in postmenopausal breast cancer patients and provided strong evidence that tamoxifen-induced changes in the nuclear proliferation marker Ki67 can act as a surrogate marker of tamoxifen response. An advantage of this study design is that all patients contribute data to the end-point analyses which included changes in Ki67 and objective clinical response as defined by the WHO criteria. We therefore genotyped patients from IMPACT for variants in the enzyme (cytochrome p450 2D6 (CYP2D6)) responsible for the conversion of tamoxifen to its potent anti-estrogenic metabolite endoxifen, as well as the enzyme responsible for the detoxification and inactivation of endoxifen via conjugation (UDP-glucuronosyltransferase 2B7 (UGT2B7).Results: Depending on their CYP2D6 variant genotype, patients were assigned an 'activity score' based on predicted allele activities from 0 (no activity) to 2 (high activity). Patients were also tested for the UGT2B7*2 variant, which has lower enzymatic activity and is therefore correlated with higher serum endoxifen concentrations. Of the 135 patient samples available for genotype determinations, 123 and 134 we evaluable for CYP2D6 and UGT2B7, respectively. There was no evidence of an association between CYP2D6 score, as determined by genotype alone, with suppression of Ki67 after 2 or 12 weeks, or with objective clinical response after 16 weeks of therapy in the tamoxifen alone, anastrozole alone or combination groups. Furthermore, this lack of association was not altered by adjustment of the CYP2D6 score for concomitant medications, known to inhibit CYP2D6 and to correlate with lower serum endoxifen concentrations. Lastly, while a statistical test for a potential interaction between CYP2D6 genotype and UGT2B7 genotype was negative, there was a marginally statistically significant association between UGT2B7 genotype alone with suppression of Ki67 after 2 weeks in the tamoxifen only group.Conclusion: Although this was a small study, these data do not support the hypothesis that patients must have active CYP2D6 in order to benefit from tamoxifen therapy. Larger more definitive studies are underway to test the effects of drug metabolizing enzymes on anti-estrogen therapies.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2011.
Early Assessment of Proliferation by the Genomic Grade Index (GGI) Predicts Response to Neo-Adjuvant Letrozole.
Authors: Singhal S. , Bedard P. , Ignatiadis M. , Haibe-Kains B. , Desmedt C. , Loi S. , Evans D. , Dixon J. , Miller W. , Sotiriou C. 
Published: December 2010

Abstract
Background: Expression of the proliferation antigen Ki-67 after short-term pre-surgical endocrine treatment is predictive of long-term relapse free survival in post-menopausal women with estrogen-receptor (ER) positive breast cancer (Dowsett et al., JNCI 2007). There are no established predictive markers of clinical response to neo-adjuvant endocrine therapy.Methods: Whole genome expression profiles (Affymetrix HG-U133A) from paired tumor biopsies before and after 10 to 14 days of neo-adjuvant letrozole were compared to tumor volume changes over 3 months of treatment for 52 post-menopausal women with hormone receptor positive breast cancer to evaluate early predictive markers of clinical response.Results: Clinical response was observed in 80% Luminal A (24/30) and 59% Luminal B (13/22) tumors (p=0.1). Baseline tumor proliferation assessed by GGI or Ki-67 mRNA expression were not predictive of clinical response (p=0.29 and p=0.73 respectively). The absolute value of GGI at Day 10 to 14 was predictive of clinical response (p=0.001), particularly for luminal B (p=0.001) but not luminal A (p=0.35) tumors. The change in GGI from baseline to Day 10 to 14 was marginally predictive of response (p=0.063). Absolute day 10 to 14 Ki67 mRNA expression and the change in Ki67 mRNA were not associated with clinical response (p=0.54 and p=0.58 respectively). Baseline, absolute Day 10 to 14, and change in the expression of the ER gene (ESR1) or an integrative gene module reflecting ER signaling were not predictive of clinical response.Conclusion: Expression of GGI after 10 to 14 days of neo-adjuvant letrozole and the change in GGI with short-term treatment are predictive of clinical response observed after 3 months of therapy. Early assessment of GGI may be useful to determine which post-menopausal patients with highly-proliferative ER-positive disease benefit from endocrine therapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2016.
p53 Status Splits Triple-Negative Breast Cancers in Subgroups with Distinct Predictive and Prognostic Potential Value.
Authors: Alberti S. , Ambrogi F. , Pedriali M. , Piantelli M. , Querzoli P. , Nenci I. , Ellis I. , Boracchi P. , Coradini D. , Biganzoli E. 
Published: December 2010

Abstract
Background: Triple-negative breast cancers largely encompass basal-like breast cancers, which demonstrate an aggressive clinical behaviour and poor prognosis. However, triple-negatives also include normal breast-like cancers, as identified by gene expression profiling, which have a better prognosis than basal-like cancers, but do not respond as well to neoadjuvant chemotherapy. Thus, a clear-cut distinction between the two subgroups is urgently needed. p53 is heterogeneously expressed in triple-negative cases, suggesting association to subgroups with diverse biological profiles. Hence, we comparatively analyzed p53 expression in triple-negative breast cancers from two independent case series.Material and Methods: Two independent breast tumor case series (633 cases from Ferrara University, Italy and 1076 cases from Nottingham University, UK) were analysed. Applying non-hierarchical algorithms, we have previously identified four breast tumor clusters, that possess markedly different prognosis: cluster [1], characterized by high values of ER/PR (good prognosis); cluster [2], with intermediate / heterogeneous ER/PR values (good prognosis); cluster [3], with low-to-nil ER (bad prognosis) and cluster [4] with low-to-nil PR and high HER2 values (bad prognosis) (Clin Cancer Res 2006;12:781-90). p53 expression in triple-negative cases belonging to the different clusters was analyzed.Results: p53 protein expression sharply subdivided the triple-negative Ferrara cases into two distinct subsets, that were tightly associated to clusters [2] or [3], respectively. Low-to-nil p53 levels were only observed in cluster [2] while overexpression of p53 was only seen in cluster [3].The triple-negative tumors of the Nottingham dataset were comparatively evaluated. Consistently with the data of the Ferrara case series, p53 similarly split this case series in p53-overexpressing and p53 low-to-nil triple-negative cases. p53 expression was associated with shorter relapse-free (Figure 2) and overall survival.Discussion: Our findings indicate that p53 expression can split triple negative breast cancers into sharply distinct subgroups, with critically different prognosis and prediction of drug response potential.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2018.
A Systems Analysis of Mitotic Apparatus Inhibitors Defines a Response Network for Breast Cancer.
Authors: Hu Z. , Mao J. , Huang G. , Kuo W. , Lenburg M. , Ziyad S. , Korkola J. , Bayani N. , Wang N. , Gu S. , Weber B. , Wooster R. , Gray J. 
Published: December 2010

Abstract
Deregulation of aspects of the mitotic apparatus leads to increased genome instability, carcinogenesis and aggressive tumor behavior in human and rodent model systems1. This knowledge has stimulated development of inhibitors of elements of the mitotic apparatus as anticancer agents including PLK1, CENPE, and AURKB and several are now being tested for efficacy clincially2-6. These trials and eventual clinical use will benefit from molecular markers that predict response. In order to identify such markers, we assessed quantitative responses to the agents GSK461364, GSK923295 and GSK1070916 that target PLK1, CENPE and AURKB; respectively, in a panel of 50 breast cancer cell lines. This analysis showed that basal subtype cell lines were preferentially sensitive to all three agents and that responses among the lines to the three agents were strongly correlated. This may be explained by our discovery that components of the mitotic apparatus including PLK1, CENPE and AURKB form a transcriptionally co-regulated network comprised of more than 50 genes that is preferentially active in basal subtype of breast cell lines and primary tumors. Remarkably, this network also is activate in subsets of cancers of the lung, ovarian, prostate and brain, Wilms tumor, human blood malignancies and selected normal tissues. We then defined a mitotic apparatus network index (MANI) and showed that high MANI was associated with poor outcome clinically and with preferential responsive to GSK461364, GSK923295 and GSK1070916 in preclinical models. This suggests that measures of the MANI will identify poor outcome tumors that will likely respond well to mitotic apparatus network gene inhibitors as well as potential dose limiting normal tissues.Reference1. Quigley, D.A. et al. Nature 458, 505-8 (2009).2. Strebhardt, K. & Ullrich, A. Nat. Rev. Cancer 6, 321-330 (2006).3. Toyoshima-Morimoto, F., Taniguchi, E., Shinya, N., Iwamatsu, A. & Nishida, E. Nature 410, 215-20 (2001).4. Barr, F.A., Sillje, H.H. & Nigg, E.A. Nat. Rev. Mol. Cell. Biol. 5, 429–440 (2004).5. McInnes, C. et al. Nat. Chem. Biol. 2, 608–617 (2006).6. Yamada, S. et al. Oncogene 23, 5901-5911(2004).
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2020.
PI3K Pathway Activity and Response to First-Line Chemotherapy in Combination with Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer.
Authors: Vorkas P. , Agelaki S. , Poumpouridou N. , Poumpouridou N. , Kroupis C. , Kroupis C. , Mavroudis D. , Stathopoulos E. , Georgoulias V. , Lianidou E. 
Published: December 2010

Abstract
Background. Not all patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) respond to trastuzumab and most that initially respond, ultimately develop resistance to treatment. Activated PI3K signalling has been proposed to predict trastuzumab resistance.Patients and Methods. PI3K pathway activity was evaluated in tumor samples from pts with HER2-overexpressing MBC treated with first-line chemotherapy in combination with trastuzumab by: a) assessing PIK3CA mutation status by our recently developed High Resolution Melting Analysis (HRMA) for the detection of mutations in exons 9 and 20, performed in the HR-1 High Resolution Melter (Idaho Technology, USA) and b) PTEN expression levels using immunohistochemical analysis. All samples with mutant melting transitions were verified by DNA sequencing. PI3K pathway activation defined by the presence of PIK3CA hotspot mutations and/or low or absent PTEN was correlated to the response to trastuzumab-based therapy.Results. Fifty-six pts received trastuzumab in combination with vinorelbine (n=15) or taxane-based chemotherapy (n=41). Median age was 62 years, 55 pts (98.2%) had PS 0-1, 10 (17.9%) were premenopausal, 27 (48.2%) had hormone receptor negative tumors and 37 (66.1%) had visceral metastases. HRMA identified the presence of PIK3CA mutations in 22 (39.3%) pts [exon 9 mutations in 5 (8.9%) and exon 20 mutations in 17 (30.4%) pts]. Subsequent PIK3CA sequence analysis demonstrated exon 9 mutations (E542K and E545K) in 4 (7.1%) pts and exon 20 mutations in 17 (30.4%; H104R in 16, and H1047L in 1) corresponding to a PIK3CA hotspot mutation frequency of 35.7%. Only in one sample that showed a mutant melting transition by HRMA, DNA sequencing did not confirm the presence of a PIK3CA mutation in exon 9, possibly due to lower sensitivity. Absent or reduced PTEN expression was detected in 22 (39.3%) of 47 pts. In 9 (16.1%) pts, PTEN score could not be retrieved. A trend for lower response rates was observed for patients with PI3K hotspot mutations compared to pts with wild-type tumors (35% vs 60%, p= 0.074). No difference in response rates was identified for pts with low or absent compared to normal PTEN expression (p=0.920). However, activated PI3K pathway (presence of PI3K mutations and/or low or absent PTEN expression) was associated with significantly lower response rates compared to non-activated one (40.6% vs 72.2%; p=0.032).Conclusions. The activation of PI3K pathway is predictive of response to first-line chemotherapy plus trastuzumab in pts with HER2-overexpressing MBC.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2022.
Multiple Subtypes of HER-2/Neu-Positive Metastatic Breast Cancer.
Authors: Lipton A. , Leitzel K. , Koestler W. , Fuchs E. , Singer C. , Ali S. , Huang W. , Sperinde J. , Goodman L. , Jin X. , Banerjee J. , Weston J. , Mukherjee A. , Larson J. , Weidler J. , Paquet A. , Williams S. , Winslow J. , Parry G. , Bates M. 
Published: December 2010

Abstract
Background: Using IHC or FISH to select patients for trastuzumab-based therapy, only half of HER2-positive patients show evidence of response. In vitro data implicate HER2:HER3 heterodimers and p95HER2 (p95), the truncated 95-kilodalton C-terminal fragment of HER-2 lacking the trastuzumab binding site, as mediators of resistance to trastuzumab at the receptor level. We have previously reported that central FISH-positive patients with low HER2 protein expression by VeraTag had significantly reduced response to trastuzumab compared to patients who had FISH-positive tumors with high HER2 protein expression (Lipton, SABCS 2008). Adding quantitative measurements of HER3 and p95, we offer evidence for the existence of multiple sub-types of HER2-positive tumors that respond differently to trastuzumab.Methods: Using the VeraTag assay, quantitative protein measurements of HER2, HER3, and p95 were made in FFPE specimens from a cohort of patients with metastatic breast cancer (MBC) and correlated with time to progression (TTP) and overall survival (OS) following treatment with first-line trastuzumab using Kaplan-Meier (KM) and Cox proportional hazards regression analyses.Results: Measurements of HER2 (H2T), HER3 (H3T) and p95 were made in FFPE tumor samples from 95 patients treated with first-line trastuzumab for metastatic breast cancer. Within the group that overexpressed HER2 by the VeraTag Assay (n=60), a group with highly overexpressed HER2 (n=15) had shorter TTP and OS than those that had moderate HER2 overexpression (median TTP 4.6 vs. 12 mos, HR=2.1; p=0.011; median OS 29 vs. 40 mos, HR=2.0; p=0.047). Within the subgroup with moderate H2T overexpression (n=45), bivariate Cox analyses demonstrated that p95 and H3T were independent predictors of TTP (p95 HR=2.1; p=0.031; H3T HR=3.5; p=0.0037). For OS, p95 was significant and H3T showed a strong trend (p95 HR=2.5; p=0.025, H3T HR=2.2; p=0.089). Univariate KM analysis with the p95+ and H3T+ groups combined, gives the results in the table below. These data suggest that HER2-positive breast cancer patients can be classified into at least 4 sub-groups with different outcomes following trastuzumab treatment.Conclusions: These data suggest the existence of multiple subgroups of HER2-positive patients expressing varying HER2, p95, and HER3 levels that experience different clinical outcomes following treatment with trastuzumab. Furthermore, the association of HER3 and p95 overexpression with poor response to trastuzumab in otherwise HER2-positive tumors suggests possible treatment approaches with combinations of targeted therapies.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2030.