bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and Activity Report of a Randomized Phase II Trial of Preoperative Anthracycline-Based Chemotherapy Plus Lapatinib, Trastuzumab or Both in HER2 Positive Breast Cancer: CHERLOB Trial.
Authors: Guarneri V. , Frassoldati A. , Bottini A. , Cagossi K. , Piacentini F. , Ravaioli A. , Cavanna L. , Amadori D. , Bisagni G. , Giardina G. , Conte P. 
Published: December 2010

Abstract
Introduction: We have designed a randomized phase II trial of preoperative sequential taxanes-anthracyclines in combination with trastuzumab, lapatinib, or both trastuzumab and lapatinib in HER2 positive, stage II-IIIA breast cancer patients. Primary aim of the study is the percentage of pathological complete response (pCR) as defined as complete disappearance of invasive tumor in both breast and axillary nodes.Methods: chemotherapy (CT) consists of paclitaxel 80 mg/m2 weekly x 12 weeks followed by FE75C x 4 cycles administered every 3 weeks. Patients randomized to arm A receive CT plus weekly trastuzumab; in arm B patients receive CT plus lapatinib 1500 mg po daily; in arm C patients receive CT plus weekly trastuzumab and lapatinib 1000 mg po daily. Trastuzumab and lapatinib are administered throughout the entire CT plan. The study sample size has been calculated according to the two steps Simon's design. The overall planned accrual is 120 patients. Following the second safety report from the Independent Data Monitoring Committee on the first 30 evaluable patients, due to the occurrence of grade 3 diarrhea in 20% and in 41% of the patients randomized to arm B and C respectively, lapatinib doses have been reduced to 1250 mg in arm B and 750 mg in arm C.Results: 66 patients have been randomized: 20 in arm A, 20 in arm B, and 26 in arm C. Median age is 50 years (range 27-66). The overall non hematologic toxicity of grade (G) &gt;1, as reported as maximum toxicity per patient, is as follows: diarrhea G2 29%, G3 22%; skin rash G2 29%, G3 7%; hepatobiliary events G2 10%, G3 5%, G4 3%.Left ventricular ejection fraction (LVEF) has been evaluated at baseline, after 12-13 weeks, and at the end of therapy. Mean LVEF% (range) was 62% (52%-77%), 61% (44%-78%) and 61% (53%-74%) respectively. No patient had symptomatic cardiac events. Forty-five patients underwent surgery, and are evaluable for response: 67% of the patients received breast conserving surgery. A pCR in breast and axillary nodes has been observed in 39% of the cases.Conclusions: The study accrual is ongoing. The safety of patients randomized following the amendment reducing lapatinib dosage will be presented at the Meeting. Supported by GlaxoSmithKline
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1093.
The Golgi Associated Calcium Pumps in Human Breast Cancer.
Authors: Grice D. , Faddy H. , Kenny P. , Monteith G. , Roberts-Thomson S. 
Published: December 2010

Abstract
The Golgi apparatus, located within the cell, is an intracellular calcium store. Golgi calcium is implicated in roles including post-translational modification, cell signalling and cellular proliferation. In breast cancer, there is evidence of aberrations in Golgi-dependent processes, some of which are linked to calcium regulated enzymes and Golgi structure. Previous studies show that Golgi-associated calcium pumps sequester calcium into the Golgi apparatus via an active transport mechanism requiring ATP. We investigated Golgi-associated calcium pumps in the context of breast cancer. Analysis of clinical breast sample and breast cancer cell line microarray databases indicates that different breast cancer subtypes may be characterized by alterations in Golgi calcium signalling. To explore this further, we assessed calcium transporter transcription in a bank of breast cancer-derived cell lines and non-malignant-derived breast cell lines using real time RT-PCR. The consequences of silencing Golgi calcium transporter expression were assessed using Dharmacon Smartpool On Target Plus siRNA. Inhibition (greater than 90%) was confirmed with real time RT-PCR 24, 72, 96 and 120 hours post transfection (P &lt; 0.05). Effects of inhibition on calcium signalling, proliferation and induction and sensitization of breast cancer cells to endoplasmic reticulum stress via tunicamycin (0.1, 1, 10 µg/mL) was assessed. Endoplasmic reticulum stress was confirmed by measuring the induction of GRP94 mRNA expression. Effects on calcium signalling were characterized using a fluorescence imaging plate reader (FLIPR; Molecular DevicesTM) and a fluorescence calcium indicator. The nature of calcium responses to endoplasmic reticulum calcium mobilizing agents was assessed, agents included a sarcoplasmic-endoplasmic Ca2+-ATPase inhibitor, a purinergic agonist (ATP, 100 µM) and a protease activated receptor modulator. Collectively our results imply that some breast cancers are associated with a remodelling of Golgi calcium transport with functional consequences on calcium signalling in breast cancer cells. Modulators of Golgi calcium content in breast cancer may represent a novel therapeutic approach for some breast breast cancer subtypes.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1129.
An Investigation into a Panel of Isogenic Taxane Resistant Breast Cancer Cell Lines Using Transcriptomic and Genomic Methods.
Authors: Kenicer J. , Lambros M. , Sabine V. , Reis-Filho J. , Bartlett J. 
Published: December 2010

Abstract
Background: Taxanes are a powerful chemotherapeutics used to treat breast cancer. Taxane resistance has become increasingly more prevalent in the clinic; This problem is exacerbated by a lack of understanding of mechanisms underlying taxane resistance.Materials and Methods: 3 isogenic breast cancer cell-line panels: paclitaxel resistant (PACR) MDA-MB-231s/ZR75-1s and docetaxel resistant (DOCR) ZR75-1s were derived by culturing cells in incrementally escalating doses of taxanes over time. MDA-MB-231: native, 5nM, 25nM and 100nM PACR cells, ZR75-1: native, and 5nM, 25nM, and 50nM PACR and ZR75-1: native, and 5nM, 25nM and 50nM DOCR cells were analysed. RNA from native and PACR MDA-MB-231 cell lines was analysed on the Illumina® human ref.8V2 chip. Data were analysed using IlluminaGui. For aCGH, DNA was extracted from MDA-MB-231 PACR, ZR75-1 PACR and DOCR and respective parental lines, labelled and hybridised to a tiling path BAC microarray (resolution ∼50kb). Each cell-line was tested against reference samples of DNA from pooled female blood. Taxane resistant cells were tested against their parental cell line.Results: Illumina data demonstrated that resistance to increasing doses of paclitaxel is associated with sequential increases in mRNA dysregulation in MDA-MB-231 cells.A number of comparisons between the illumina data of native and the PACR cells were made using a p value of P≤0.001. The first comparison made using the illumina data, was between the 5nM PACR cells and the native cell lines: 25 significantly up or downregulated genes were identified. When the 25nM PACR cells were compared to the native cell lines, 225 genes were found to be significantly up or downregulated. Finally, when 100nM PACR cells were compared to native cells, 425 genes were found to be significantly up or downregulated. A group of genes identified that were common to multiple paclitaxel resistant groups included candidates such as YY1, AURKA and CCND2. aCGH has identified significant differences in patterns of copy number loss, gain and amplification in the taxane resistant cell lines, including chromosome loss of 6p and gain of 2p. Illumina and aCGH data were overlaid using specially designed algorithms.Discussion: Both aCGH and expression arrays highlight a progressive acquisition of molecular and transcriptomic alterations in isogenic breast cancer cell lines resistant to increasing doses of taxanes. Further mapping of transcriptomic and genomic profiles will enable identification of key molecular targets for restoration of taxane sensitivity. Genes upregulated in taxane resistant clones identified in the illumina experiment, in particular those whose upregulation is underpinned by DNA copy number gains in resistant cells, may represent genes which may be targeted with inhibitors to test potential candidates for reversing taxane resistance.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1134.
Frequency of PIK
3CA Mutations in Chinese HER2+ Metastatic Breast Cancer Patients and Association with Clinical Benefit to Lapatinib and Capecitabine Treatment.
Authors: Xu B. , Zefei J. , Chua D. , Shao Z. , Luo R. , Wang X. , Yuan P. , Newstat B. , Liu Y. , Gagnon R. , Chi H. , Martin A. , Stein S. , Wang L. 
Published: December 2010

Abstract
Background: Activating mutations in PIK3CA are frequent in breast cancer (Campbell et al. Cancer Res 2004;64:7678-7681). Previous analyses suggest that the presence of PIK3CA activating mutations were associated with poor clinical outcome (Li et al. Breast Can Res Treat 2006;96:91-95) and could confer resistance to treatment with trastuzumab (T) (Berns et al. Cancer Cell 2007;12:395-402). Lapatinib (L) is an oral tyrosine kinase inhibitor targeting EGFR and HER2 pathways. L plus capecitabine (C) has demonstrated efficacy in women with HER2+ metastatic breast cancer (MBC) previously treated with T (Geyer et al. N Engl J Med 2006;355(26):2733-2743). EGF109491 evaluated the efficacy of L+C in 52 Chinese HER2+ MBC patients. The clinical benefit rate (CBR) was 57.7% (PR 44% and SD 44%) and median progression free survival (PFS) was 6.3 months. The purpose of this analysis was to establish the frequency of PIK3CA mutations in this small cohort of Chinese patients and to determine if the presence of a PIK3CA mutation has any impact on clinical benefit to L+C.Methods: 38/52 patients provided tumor samples for biomarker analysis. Briefly, DNA was extracted from these tumor samples, amplified by PCR and sequenced by Pyrosequencing methods to identify the presence of frequent activating mutations in exons 9 and 20 in PIK3CA. Mutation status was tested for association with CBR and PFS using contingency table analysis and proportional hazards analysis respectively.Results:11/38 (29%) patients harbored a mutation in the PIK3CA gene, consistent with published frequencies. 9/11 mutations reside in the catalytic domain and 2/11 mutations reside in the accessory domain of the gene. There was no statistical association with CBR (p=0.639) or PFS (HR=1.01, p=0.989) in PIK3CA wildtype patients vs. PIK3CA mutant patients. PIK3CA wildtype n=27 (%)PIK3CA Mutation n=11 (%)CR0 (0)0 (0)PR12 (44%)4 (36%)SD13 (48%)5 (45%)PD1 (4%)1 (9%)Unknown1 (4%)1 (9%)HR1.01 (p=0.989) Conclusion: The frequency of PIK3CA mutations in this small cohort of Chinese HER2+ MBC patients is consistent with published frequencies. There was no statistically significant association between the presence of a PIK3CA mutation and clinical benefit to L+C in these patients. These results are in agreement with previous reports that mutations in PIK3CA do not seem to impact clinical outcome following L-containing treatment regimens.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1140.
The Isoform Selective Histone Deacetylase Inhibitor Entinostat Is Active in Primary Human Triple-Negative Breast Cancer Models.
Authors: Ordentlich P. , Hoffman J. , Doser T. , Tee L. , Huynh Y. , Mee S. , Mamuszka H. , Lee G. 
Published: December 2010

Abstract
Background: Triple-negative (ER, PR, HER2 negative) breast cancer represents an unmet need for which novel agents and approaches are essential. Entinostat is an oral, class 1 isoform selective histone deacetylase inhibitor currently in multiple phase 2 clinical studies including advanced NSCLC and breast cancer. Previous studies have a) established the anti-proliferative activity of entinostat in the triple negative cell line model MDA-MB-231 b) shown that entinostat induces expression of ERα and c) that entinostat is synergistic with aromatase inhibitors to inhibit tumor growth of ER negative cancer cells. The aim of these studies was to validate the activity of entinostat in highly predictive primary human tumor models of triple negative breast cancer.Methods: Two approaches have been taken. First, entinostat was tested in the Oncotech Extreme Drug Resistance (EDR) proliferation assay using ten cryopreserved breast tumor explants known to lack ER, PR and HER2/neu expression by immunohistochemistry (IHC). Second, entinostat was tested at 5, 15, 30 mg/kg/d in two xenograft models using tissue derived directly from patient tumor resections. The breast cancer models MV4151 (from a postmenopausal patient with ductal invasive breast carcinoma) and MV4586 (from a premenopausal patient with relapsed invasive lobular breast carcinoma) were negative for ERa protein, however still positive for ERa mRNA. Both xenograft tumors did not express ERb. The tumor doubling times in nude mice were between 10 and 30 days. Both tumors are HER-2 negative (determined by IHC).Results: Dose response curves of entinostat were analyzed and compared to paclitaxel at 2.45 µM in ten triple negative breast tumor explants in the EDR assay. Entinostat was broadly effective in all of the tumors tested with IC50's ranging from 10nM to 270nM which are within the clinically achievable concentrations of entinostat. Two of the breast tumors that were most sensitive to entinostat (IC50 30- 100nM) were also sensitive to paclitaxel. In contrast, entinostat inhibited (IC50 10-270nM) the growth of eight of the tumors that were resistant to paclitaxel (i.e. &lt; 50% growth inhibition at 2.45 µM). For the xenograft studies, at the time of writing, dose response data in the MV4151 model has demonstrated tumor growth inhibition by entinostat at the 15 and 30 mg/kg/d administered orally with no apparent weight loss. Ongoing experiments for which data will be presented include dose response in MV4586 as well as combinations with tamoxifen and fulvestrant in both xenograft models.Conclusions: Entinostat is an effective agent at inhibiting the growth of triple negative breast tumors in human primary tumor models. A pre-surgical clinical study to assess the activity of entinostat in triple negative breast cancer patients is planned.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1146.
Computational Dissection of Tumor Expression Profiles.
Authors: Eklund A. , Juul N. , Li Q. , Richardson A. , Szallasi Z. , Szallasi Z. 
Published: December 2010

Abstract
Gene expression profiling has yielded important insights about tumor biology that may improve treatment decisions in patients. However, it is difficult to collect a specimen of pure tumor cells, and thus microarray measurements usually reflect the contribution of tumor cells as well as stromal and other normal cells. We applied unsupervised matrix factorization methods to gene expression data to derive several sets of co-expressed genes, or signatures, that together comprise a set of independent descriptors of breast tumors. Some of these signatures correspond to specific cell types (adipocytes, lymphocytes, fibroblasts), while others reflect well-known tumor-intrinsic expression programs (ER, ERBB2, proliferation). We confirmed the specificity of the signatures using expression data from purified normal cells and tumor cell lines, microdissected tumors, and bulk tumors with corresponding histological cellularity estimates. In several data sets, cell-type signatures were highly variable and anticorrelated with tumor-intrinsic signatures, confirming that variation in normal cell content is a potential source of measurement bias.Overall, these results provide an intuitive framework for the interpetation of tumor expression profiles and may lead to an improved understanding of the physiological mechanisms involved in tumor development.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1166.
Early Acquired Resistance to Endocrine Therapy: Extending the Neoadjuvant Model.
Authors: Anderson H. , Anderson H. , A'Hern R. , Salter J. , Hills M. , Detre S. , Larionov A. , Skene A. , Miller W. , Dixon J. , Smith I. , Dowsett M. , Dowsett M. 
Published: December 2010

Abstract
Background: Neoadjuvant endocrine therapy allows biological studies of de novo response and resistance but not of acquired resistance based on clinical endpoints as surgery is usually carried out after around 4 months. Response is associated with a significant fall in Ki67 (proliferation) after 2 weeks treatment. However, at 12/16 weeks, c.15% of tumours show recovery of Ki67. We hypothesized that this recovery reflected rapidly acquired treatment resistance and have assessed its clinical relevance and association with tumour biomarkers.Methods: Ki67, ER, PgR and HER-2 (with FISH for 2+ cases) IHC measurements taken at baseline, 2 weeks and 12/16 weeks during neoadjuvant aromatase inhibitor (AI) treatment were available from three previously reported clinical trials [1-3] for a total of 177 ER+ patients. To allow pooling of data, ER and PgR levels were expressed as Allred scores. Long-term clinical follow-up data were available for 142 patients who received endocrine therapy within the IMPACT trial. Categories of response/resistance based on Ki67 change were created and patients classified accordingly: de novo resistance (&lt;50% decrease in Ki67 from baseline to 2 weeks), acquired resistance (&gt;50% decrease in Ki67 from baseline to 2 weeks, but overall fall at 12/16 weeks &lt;50%) and maintained response (&gt;50% decrease in Ki67 from baseline to 2 weeks and overall fall &gt;50%).Results: Patients defined as showing acquired resistance had significantly worse RFS than those defined as showing maintained response (HR: 3.73, 95%CI: 1.18-11.79, p=0.025) and very similar to those with de novo resistance (HR: 3.66, 95% CI: 1.41-9.50, p=0.008). More HER-2+ cases showed Ki67 recovery than would be expected by chance (acquired resistance: 5/19 HER-2+, maintained response: 5/100 HER-2+; p=0.02). There was a weak suggestion that pre-treatment ER level may be lower for patients showing Ki67 recovery than those with persistent response (p=0.11), but no evidence was seen for an effect of pre-treatment PgR level (p=0.52).Conclusions: Tumours that exhibit an early Ki67 fall followed by Ki67 recovery at 12/16 weeks are associated with poorer RFS than those showing maintained suppression of Ki67 suggesting that Ki67 may act as a valid intermediate marker of acquired resistance. HER-2 positivity is associated with development of early acquired Ki67-based resistance, but other mechanisms for early acquired resistance exist.Supported by The Mary-Jean Mitchell Green Foundation.[1] Dowsett M et al., J Clin Oncol 2005. 23(11): 2477-92[2] Smith IE et al., J Clin Oncol 2007. 25(25): 3816-22[3] Miller WR et al., J Clin Oncol 2009. 27(9): 1382-7
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2005.
Randomised Placebo Controlled Trial Studying Short Term Biological Effects of the Combination of Letrozole and Zoledronic Acid on Invasive Breast Cancer.
Authors: Bundred N. , Cramer A. , Morris J. , Landberg G. , Renshaw L. , Winter M. , Coleman R. , Grassby S. , Knox F. , Dixon M. 
Published: December 2010

Abstract
To determine whether the addition of Zoledronic Acid to endocrine therapy increases apoptosis or decreases proliferation in early invasive breast cancer, a placebo controlled randomised trial comparing 14 days treatment with Letrozole or Letrozole and Zoledronic Acid pre-operatively was performed.PatientsIn total 109 postmenopausal women with early invasive hormone receptor positive breast cancer were randomised (1:1:1) to either placebo, Letrozole 2.5mg/day or Letrozole with Zoledronic Acid 4mg single dose intravenously 2-4 days before definitive surgical excision. Epithelial proliferation and apoptosis were measured on paired baseline and surgical biopsy specimens (after 14 days of treatment) using Ki67 and Activated Caspase 3 immunohistochemistry. Alterations in angiogenic markers (VCAM/VEGF and CD31) were also studied. The primary endpoint was fall in Ki67 between diagnosis and surgical excision.ResultsOverall 109 women were enrolled but paired biopsies were only available for 101 patients. PlaceboLetrozoleLet + Zoln323435Absolute Ki67 change (median,range)-0.8 (-12,12)8.6 (-14,37)12.9 (-12,29) Caspase 3 change (median,range)0.1 (-3.8, 9.3)0.4 (-2.7, -4.1)0.2 (-10.9, -14.4) Absolute change (Cell turnover index)-0.3 (-142, -59)18.9 (-201, 192)17.7 (-14, 379) Statistically significant reductions in Ki67 and Cell Turnover Index were seen with Letrozole and Let & Zol (p ≤ 0.001) but there was no significant different between Letrozole and Letrozole plus Zoledronic Acid groups (p = 0.26). Apoptosis did not change between the three groups.ConclusionLetrozole reduces proliferation by 70% when used for 14 days prior to surgery. Zoledronic Acid administration prior to surgery is safe but when administered as a single dose at a median of 3 days before surgery did not significantly increase apoptosis or decrease proliferation compared to Letrozole alone.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2009.
Sunitinib (SU) in Combination with Trastuzumab (T) for the Treatment of Advanced Breast Cancer (ABC): Activity and Safety Results from a Phase II Study.
Authors: Blay J. , Lluch A. , Gutierrez M. , Martin M. , Kozloff M. , Prady C. , Huang X. , Verkh L. , Chen C. , Tassell V. , Kern K. , Verma S. 
Published: December 2010

Abstract
Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, FLT3, and CSF-1R, with single-agent activity in patients (pts) with heavily pretreated ABC (locally recurrent or metastatic breast cancer). T is approved for 2nd-line monotherapy and in combination with taxane-based therapies for 1st-line ABC. The combination of SU + T in HER2+ ABC pts was investigated.Materials and methods: Eligible pts with HER2+ ABC received a starting dose of oral SU 37.5 mg/d (continuous daily dosing [CDD]) and either T administered wkly (iv loading 4 mg/kg then wkly 2 mg/kg) or q3w (loading 8 mg/kg then q3w 6 mg/kg). Due to changing standard of care, the trial was amended to include pts having prior chemotherapy in the 1st-line setting. Previous treatment (tx) with T (± lapatinib) was permitted. The primary endpoint was objective response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), pharmacokinetics (PK) and quality of life (QoL).Results: As of April 2009, 60 pts were enrolled (6 on the original protocol and 54 under the amendment). Of 54 pts enrolled post-amendment, 6 pts continue on study and 48 have discontinued, 12 due to AEs. Most (n=31; 57%) pts received SU + T as 1st-line tx and 11/31 pts were completely tx-naïve. Pts received a median of 5 cycles (range: 1–16) of SU and 4 cycles (range: 1–15) of T. SU was dose reduced from 37.5 mg/d to 25 mg/d in 39% of pts. All pts were evaluable for safety and 52 pts were evaluable for efficacy. ORR was 34.6% and clinical benefit rate was 48% (2 CR; 16 PR; 7 SD ≥24 wks). Of the 18 responders, 5 pts were completely tx-naïve and 9 pts were 1st-line. Median PFS was 25.3 wks (95% CI, 19.3, 29.1). Most AEs were G1/2. G3 non-hematologic AEs in ≥10% pts were asthenia (17%) and hypertension (11%) and 3 G4 events occurred (LVEF decline, pulmonary embolism, and pancreatitis). Hematologic AEs (G3/4 in ≥10% pts) were neutropenia (22%) and thrombocytopenia (17%). One G5 event (cardiogenic shock) was reported. LVEF decline/LV dysfunction occurred in 21 pts (6 pts had ≥G3 AEs); 18/21 pts (86%) had received prior anthracycline and 12 pts (57%) prior T. There was no significant on-tx change from baseline in the QoL domain. Mean (SD) steady state level for SU was 46.1 (25.9) ng/mL in agreement with prior observations.Conclusions: The combination of SU (37.5 mg/d; CDD schedule) + T (wkly or q3w) showed acceptable tolerability and antitumor activity in HER2+ ABC pts without adversely affecting overall QoL.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 201.