bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1-12-22: Impact on Survival of the Level of HER2/neu Gene Amplification in Patients with HER2−Positive (HER2+) Advanced Breast Cancer (AdvBrCa) Treated with Trastuzumab (H).
Authors: Gullo G , Bettio D , Zuradelli M , Masci G , Giordano L , Bareggi C , Salvini P , Runza L , Santoro A 
Published: June 2012

Abstract
Background The level of HER2/neu (HER2) amplification, defined as HER2/centromeric region of chromosome 17 (CEP17) ratio at dual-color fluorescent in-situ hybridization (FISH) test presents wide variations in clinical practice but its clinical significance is still undefined. We designed this retrospective study to investigate the correlations between level of HER2 amplification in primary (T) and/or metastases (M) and outcome in a cohort of HER2+ AdvBrCa pts treated with a H-containing therapy.
Methods Retrospective multicentric study designed according to REporting recommendations for tumor MARKer prognostic studies (REMARK). To be included pts must have all the following: metastatic or locally advanced (not amenable of curative surgery) BrCa, HER2+ tumour defined as score 3+ at immunohistochemistry or FISH positive, treatment with a H-containing regimen (no H in neo- or adjuvant setting was allowed), at least one tumour sample from T and/or M available, measurable or evaluable disease, adequate follow up (FU) information.Outcome parameters included event-free survival (EFS) and overall survival (OS). All FISH tests were prospectively performed in a central laboratory of cytogenetic specifically for this study and in accordance with the international guidelines on FISH testing.
Results Ninety-one females were identified and 63 included in the final analysis. Forty-seven pts had one specimen available from T or M, 16 pts had two specimens from either T and a corresponding M. All M samples were obtained before treatment with H. Median FU time is 19.2 months (range 1.2−94.6). In 11 out of 16 cases (69%) with two tumour specimens HER2/CEP17 ratio was higher in M than in T with a statistically significant difference in the median HER2/CEP17 ratio between T (8.3, range: 3.1−18.4) and the corresponding M (10.9, range: 4.6−20.8) (p=0.004). The incremental gain in HER2/CEP17 ratio was associated with significantly shorter OS after trastuzumab-based therapy (p=0.023). A trend towards a correlation between increase in level of HER2 amplification assessed in M and shorter EFS and OS was observed. No statistically significant correlation was found between level of HER2 amplification assessed in T and EFS and OS.
Conclusions Level of HER2 amplification reported as HER2/CEP17 ratio is a dynamic parameter in HER2+ AdvBrCa as it increases from T to the matched M in a significant proportion of pts. The gain in HER2 gene copies may represent a prognostic factor for shorter OS when pts with HER2+ AdvBrCa are treated with a H-based therapy. Further studies on the level of HER2 amplification in BrCa metastases are strongly warranted to better understand the biology of HER2−positive breast cancer and to better identify patients with a poorer prognosis after treatment with H.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-22.
P1-14-02: Correlation of Circulating Tumor Cells (CTC) and Circulating Endothelial Cells (CEC) with Pathological Complete Response (pCR) during Neoadjuvant Chemotherapy (CT) Combined with Bevacizumab in HER2 Negative Inflammatory Breast Cancer (IBC): Ancillary Study of Phase II Trial BEVERLY 1.
Authors: Pierga J-Y , Bidard F-C , Andre F , Petit T , Dalenc F , Delozier T , Romieu G , Bonneterre J , Ferrero J-M , Kerbrat P , Lemonnier J , Viens P 
Published: June 2012

Abstract
Background: Prognostic value of CTC detection in blood has been reported in primary breast cancer with a rate around 20% in the neoadjuvant setting. No correlation between CTC and pCR to neoadjuvant CT in operable breast cancer has been reported (Pierga CCR 2008, Riethdorf CCR 2010). Predictive value of CEC for response to anti-angiogenic agents is unclear.
Methods: CTC and CEC were detected in 7.5 ml and 4 ml of blood respectively with CellSearch™ System in the neoadjuvant setting of HER2 negative IBC (T4d) patients (pts) enrolled in the phase II multicentre trial BEVERLY 1, evaluating bevacizumab (15mg/kg q3w) in combination with sequential neoadjuvant CT of 4 cycles of FEC followed by 4 cycles of Docetaxel. Patients received postoperatively 10 cycles of bevacizumab and hormonotherapy if tumor was ER+.
Results: From 12/08 to 09/10, 101 pts were included, 96 were evaluable for pCR and 92 for CTC and CEC. Out of 96 pts, 51 (53%) had triple negative breast cancer (TNBC). At baseline, 37 pts out of 92 had ≥ 1 detectable CTC (40%, 95%CI 30–50%).

At baseline, CTC level was not correlated with CEC level, neither with TNBC nor pCR. A drop in CTC incidence was observed from baseline to the 1st follow-up analysis after 4 cycles (p&lt;0.0001). Out of 6 pts with detectable CTC at the end of adjuvant bevacizumab (8 months post surgery) none had pCR (p=0.05 Yates test). There was a significant increase of CEC from baseline to presurgery sample (p &lt;0.001) and a decrease (p=0.04) after tumor removal and end of CT. A higher level of CEC (&gt;20/4ml) before C5 could be associated with a higher probability of pCR (Khi2 test, p=0.003).
Conclusions: We observed a high CTC detection rate of 40% in HER2− IBC, including TNBC. CEC levels increased progressively during neoadjuvant treatment and decreased after its interruption. Baseline CTC and CEC levels were not predictive of pCR. Detection of CTC at 8 months of follow-up was associated with the absence of response to neoadjuvant chemotherapy.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-14-02.
P1-14-03: AVALUZ Study: First Line with Bevacizumab in Combination with Paclitaxel (P) and Gemcitabine (G) in Patients with HER-2 Negative Recurrent or Metastatic BC: PFS Analysis.
Authors: Salvador J , Ciruelos E , Codes de Villena M , Jaen A , Gil M , Galan A , Murias A , Jara C , de la Haba J , Baena JM , Villanueva MJ , Bayo J , Blancas I , Gonzalez E , Perez D , Mel JR , Manso L 
Published: June 2012

Abstract
Background The combination of bevacizumab (B) with taxanes, capecitabine or anthracyclines has shown increased PFS in pts with mBC. The combination with G and P has been evaluated and has demonstrated high response rate and good toxicity profile. The aim of this study is to evaluate the efficacy and toxicity profile of the combination of B with G and P, providing an update of PFS and the toxicity experienced in all patients treated.
Methods A phase II multicenter, national, open-label study in pts diagnosed of recurrent or metastatic HER-2 negative BC, treated with first line B 10 mg/kg, P 150 mg/m2 and G 2000 mg/m2 day 1 and 15 c/28 d until progression disease, unacceptable toxicity or medical decision. This abstract evaluates efficacy by PFS as primary endpoint and as secondary endpoints: response rate and toxicity profile (NCI CTC v3.0 criteria).
Results From January 2009 to December 2009, 82 evaluable patients were recruited in 23 sites. The characteristic of the all of patients included (90) are: median age 51.5 (26-81), ER + 68%, PR + 59%, triple negative pts 19%, previous chemotherapy (neoadj or adj) 64.4% and ≥ 3 metastatic sites 21% of patients (19). The median cycles administered per pts was 7 (1-26) and the relative median dose intensity was 0.93 for B, 0.89 for P and 0.91 for G.
Of the 75 patients with response assessment, the overall response rate obtained was 72% with a clinical benefit of 89.3% (80.6−95.28%) (CR 14.7% (11), PR 57.3% (43), SD 17.3% and PD 10.7%). Of the 82 patients with a median follow up of 16.5 m (0.16- 26.38), preliminary median PFS (43% events) for these pts was 11.48 m (8.98−15.72), the median duration of first response (MDR) was 12.4 m (7.47-NA) and the median OS was 21.35 m (20.72- NA). The one year OS% was 84.15% (74.27 - 90.47).
Toxicity was generally manageable. Related AEs have been reported in 67/82 patients which were mostly mild or moderate. Safety analysis revealed 24 SAEs in 21 patients.
Conclusions Bevacizumab in combination with paclitaxel and gemcitabine showed significant PFS compared with the published data with paclitaxel and gemcitabine and high clinical benefit with manageable safety profile.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-14-03.
P1-17-04: Phase I Study of PARP Inhibitor ABT-888 (Veliparib) in Combination with Cisplatin and Vinorelbine for Patients with Advanced Triple Negative Breast Cancer and/or BRCA-Mutation Associated Breast Cancer.
Authors: Rodler ET , Specht JM , Gadi VK , Kurland BF , Griffin MJ , Hammond JJ , Gralow JR 
Published: June 2012

Abstract
Background: Inhibitors of poly(ADP-ribose) polymerase (PARP) have shown preclinical and clinical activity in targeting tumors with pre-existing DNA repair defects, in particular BRCA1 and BRCA2 deficient tumors. Cisplatin (CP) has demonstrated synergy with ABT-888 (veliparib) in breast cancer xenograft models and has anti-tumor activity in triple negative (TN) and BRCA-1 deficient breast cancer. Vinorelbine (V) combined with CP has shown safety and efficacy in patients with pretreated metastatic breast cancer.
Methods: We are conducting a phase I study to determine the maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic profiles (PD), and preliminary anti-tumor activity of veliparib in combination with CP and V in patients (pts) with metastatic breast cancer who are either TN or who have BRCA1 or BRCA2 mutation associated breast cancer. Cohorts receive escalating doses of ABT-888 orally BID days 1–14, CP 75 mg/m2 intravenously (IV) day 1 and V 25 mg/m2 IV days 1,8 every 21 days, in a 3+3 design.
Results: As of 6/14/11, 18 eligible female pts have been enrolled. The median age at registration was 50 years (range 34–78 years). Sixteen pts received at least one prior metastatic regimen (range 0–8). Three pts had previously treated brain metastases. BRCA mutation status was as follows: BRCA1+ (3 pts); BRCA2+ (2 pts); confirmed mutation negative (8 pts); unknown (5 pts). Four pts received the 20 mg BID veliparib dose (one patient in the cohort died of progressive disease early in cycle 1 and was replaced), 3 received 30 mg BID, 6 received 40 mg BID, and 5 have been enrolled at dose level 4 (60 mg BID). Dose limiting toxicities occurred in one patient at the 40 mg BID dose (grade 4 thrombocytopenia), and one patient at the 60 mg BID dose (grade 3 neutropenic fever). Adverse events are typical for a platinum-based chemotherapy regimen and include nausea, fatigue, thrombocytopenia, and neutropenia. MTD has not been reached. Of 11 pts evaluable for radiographic response to date, 6 (55%) had a PR (3 of whom have a BRCA mutation) and 5 (45%) had stable disease. Correlative studies will use immunohistochemistry and gene expression array to evaluate the profile of TN breast cancer and predictors of response to treatment.
Conclusion: Veliparib in combination with CP and V has been generally well tolerated to date. Objective anti-tumor activity was seen in BRCA mutation carriers and in pts with sporadic TN breast cancer. PK, PD, and biomarker analysis is underway. Enrollment continues in the dose escalation cohorts.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-04.
P2-01-09: Gene Expression Alterations in the Lymph Node Microenvironment in Response to Successful Metastatic Colonization.
Authors: Ellsworth RE , Valente AL , Kane JL , Ellsworth DL , Shriver CD 
Published: June 2012

Abstract
Background: Breast stroma is known to play an active role in tumorigenesis, undergoing both phenotypic and molecular changes to facilitate and promote tumor development and growth. The metastatic microenvironment also plays a role in successful colonization; however, the genetic changes in these secondary microenvironments associated with metastasis are not well described.
Methods: Women with invasive breast cancer with at least one lymph node with macrometastases and one lymph node with no detectable metastases were identified from the Clinical Breast Care Project. Lymph node tissue was microdissected from both the metastatic lymph node microenvironment and negative nodes and hybridized to U133A 2.0 gene expression arrays. Differential expression was detected using Partek® Genomics Suite™6.5 using a cutoff of P&lt;0.001, &gt;2-fold change.
Results: Nineteen genes were differentially expressed between negative lymph nodes and lymph node tissue microdissected from lymph nodes with metastatic tumors. Eleven genes, including EPCAM, KRT19 and MUC1 were expressed at significantly higher levels in lymph node tissue from metastatic lymph nodes while eight genes, such as CXCL2 and CXCL5, were expressed at significantly higher levels in negative lymph nodes. Results have been validated in external sample sets for AZGP1, CLEC4M, CXCL2, EPCAM, MUC1, PIP and TFPI.
Conclusions: Lymph node tissue differs in gene expression between those harboring metastatic tumors and those without metastasis. Genes expressed at higher levels in lymph nodes with macrometastases are involved in tumorigenesis, suggesting that like the breast stromal microenvironment, the metastatic microenvironment undergoes crosstalk with the tumor cells. In addition, a cluster of genes involved in immune function are expressed at lower levels in metastatic lymph nodes, suggesting that suppression of proper immune response may be required for successful metastatic colonization.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-09.
P2-01-19: Expression of Receptor Like Protein Tyrosine Phosphatases mu (PTPRM) in Breast Cancer and the Biological Effects of PTPRM on Breast Cancer Cells.
Authors: Sun P-H , Ye L , Mansel RE , Jiang WG 
Published: June 2012

Abstract
Introduction: Protein tyrosine phosphatases (PTPs) play a major role in many cellular functions including cell survival, proliferation, differentiation and motility. The receptor-like protein tyrosine phosphatase mu (PTPRM) has a similar structure to cell-cell adhesion molecules and has been shown to exhibit homophilic binding and confer cell-cell adhesion in cells including epithelial and cancer cells. However, the role played by PTPRM in breast cancer remains unclear. The present study investigated the expression of PTPRM in breast cancer and the biological impact of PTPRM on breast cancer cells.
Methods: Expression of PTPRM protein and gene transcript was examined in a cohort of primary breast cancer tumours. The association of PTPRM transcripts level and pathological and clinical aspects was then analysed. Expression of PTPRM transcript in breast cancer cells were knocked down using a specific anti-PTPRM transgene. The impact of PTPRM knockdown on breast cancer was evaluated using a series of in vitro cell models and in vivo tumour model.
Result: PTPRM protein was seen generally distributed in the breast tissues, including tumours and normal background tissues. A stronger staining was revealed in cytoplasm of both mammary epithelia and cancer cells in comparison with the surrounding stromal cells. A significantly decrease was seen in poorly differentiated tumours (92.5±279), and moderately differentiated tumours (288±110), compared with that of well differentiated (472±114), p=0.011 and p=0.031 respectively. PTPRM transcript levels were decreased in patients died from breast cancer. The expression of PTPRM transcripts was significantly associated with disease free survival. Patients with lower expression of PTPRM had shorter survival compared with those with high level of PTPRM expression (p=0.029). Knocking down PTPRM from breast cancer cells significantly increased cell adhesion compared with control cells (p&lt;0.001). Likewise, the knockdown also marked increase the rate of cell migration (102.9±11.3μm for control vs 115.3±10.5μm for PTPRM knockdown, p&lt;0.05).
Conclusion: The expression of PTPRM transcripts is decreased in poorly differentiated breast tumours and is correlated with poorer long term survival. This is likely to be contributed to by the biological impact of PTPRM on the aggressiveness of breast cancer cells.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-19.
P2-01-20: Reduced Plakoglobin Expression Increases the Metastatic Potential of Breast Cancer Cells.
Authors: Ottewell PD , Whitworth J , Cross SS , Nutter FH , Holen I 
Published: June 2012

Abstract
The majority of deaths from breast cancer are a result of metastases, however, little is understood about the genetic alterations underlying their onset. A recent study of human breast cancer biopsies showed alterations of expression of 9 genes in primary tumours that had metastasized compared to benign tumours. Of these, plakoglobin was the most altered, with metastatic tumours showing a 3x decrease in expression compared to benign. Furthermore, expression of plakoglobin is reduced upon autocrine production of human growth hormone, which is associated with increased breast tumour cell invasion in vivo. Plakoglobin codes for the adhesion protein gamma catenin, an integral part of the cadherin-catenin complex involved in cell-to-cell adhesion. The aim of the current study is to investigate the effects of plakoglobin knockdown on cell proliferation, migration, adhesion and invasion in vitro and in vivo.
The non-metastatic human breast cancer cell lines MCF7 and T47D that express high levels of plakoglobin and gamma-catenin were stably transfected with miRNA to two different regions of the plakoglobin gene, or scramble vector, to produce plakoglobin knockdown and controls for each cell line. Plakoglobin gene expression was monitored by qPCR and gamma-catenin expression by Western blot. Cell proliferation was assessed 24, 48, 72 and 96 hours post seeding; cell migration and invasion were measured over 24 and 48 hours using scratch and modified Boyden Chamber assays. Cell-cell adhesion was assessed by spheroid formation in agar matrix. For in vivo experiments, MCF7 plakoglobin knockdown and control cells were inoculated into the 5th and 10th mammary fat pads of 12-week old female balb/c mice (n=10 per group). Tumour growth was monitored by caliper measurements and local invasion was investigated 6 weeks after tumour inoculation on histological sections. Shedding of tumour cells into the blood stream and evidence of metastatic bone lesions was monitored by flow cytometry and μCT, respectively.
Plakoglobin and gamma catenin expression were reduced by more than 80% in all knockdown cell lines used but were unaltered following transfection with the scrambled vector. Furthermore, knockdown of plakoglobin did not effect expression of its binding partner, e-cadherin. Reduced expression of plakoglobin resulted in a more than 3-fold increase in MCF7 and T47D cell proliferation in vitro (p&lt;0.005) and a 2-fold increase in MCF-7 proliferation in vivo (P&lt;0.05), compared with control. In addition plakoglobin knockdown cells showed a 6 - 15 fold increase in invasion through basement membrane (p&lt;0.005), a 2-fold increase in migration (p&lt;0.005) and exhibited reduced cell-to-cell adhesion compared with control cells. Data show that decreased expression of plakoglobin increases the early pro-metastatic behaviour of cells including increased cell proliferation, migration and invasion.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-20.
P2-03-02: An IGF1R Antibody Does Not Inhibit Growth of Tamoxifen Resistant MCF-7 Cells.
Authors: Fagan DH , Yee D 
Published: June 2012

Abstract
The role of the insulin-like growth factor (IGF) system in breast cancer has been well defined, and inhibitors of this pathway are currently in clinical trials. The majority of anti-IGF1R clinical trials are in estrogen receptor-positive patients who have progressed on prior endocrine therapy with some early reports showing no benefit for addition of IGF1R inhibitors to endocrine therapy. The effect in endocrine-resistant models, mimicking the clinical trial scenario, has not been adequately investigated. To examine the effectiveness of IGF1R inhibitors in vitro, tamoxifen-resistant (TamR) cells were generated by culturing MCF-7L cells in the presence of 4-hydroxy-tamoxifen for more than 1 year. TamR cells had diminished levels of IGF1R with unchanged levels of insulin receptor (IR), and enhanced phosphorylation of Akt. Further, TamR cells failed to further respond to IGF-I-induced Akt activation while retaining responsiveness to both insulin and IGF-II. Additionally, IGF-I failed to enhance the proliferation and anchorage-independent growth of TamR cells; however, both insulin and IGF-II stimulated proliferation and anchorage-independent growth. An IGF1R antibody (dalotuzumab) was able to inhibit IGF-I-mediated Akt phosphorylation, proliferation, and anchorage-independent growth in parental MCF-7L cells and had minimal effect on insulin and IGF-II stimulation. In TamR cells, dalotuzumab failed to inhibit proliferation or anchorage-independent growth in response to either insulin or IGF-II. An IGF1R tyrosine kinase inhibitor, (AEW 541) with equal potency for the IGF1R and IR, inhibited IGF-I-, IGF-II-, and insulin-stimulated Akt phosphorylation, proliferation, and anchorage-independent growth in MCF-7L parental cells. Interestingly, AEW 541 also inhibited insulin- and IGF-II-stimulated Akt phosphorylation, proliferation, and anchorage-independent growth in MCF-7L TamR cells. We conclude that cells selected for tamoxifen resistance in vitro have downregulated IGF1R making antibodies directed against this receptor ineffective. Preliminary studies in vivo, suggest that initial co-treatment with tamoxifen plus dalotuzumab was more effective than either drug alone. In contrast, acquired tamoxifen resistance might require dual inhibition of IGF1R and PI3K targets to completely suppress IGF system signaling as currently under study in the clinic. Alternatively, IGF1R tyrosine kinase inhibitors may be effective by inhibiting both IGF1R and IR signaling in cells selected for tamoxifen resistance.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-03-02.