bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1-04-05: T-DM1 and Pertuzumab as New Tools for HER2 Specific Antibody-Therapy Against Breast Cancer Stem Cells in HER2−Positive Mammary Carcinoma.
Authors: Honig A , Diessner J , Dietl J , Wischhusen J 
Published: June 2012

Abstract
Trastuzumab (Herceptin®) has significantly improved the overall survival of patients with HER2−positive breast cancer. The efficacy of this treatment depends significantly on antibody-dependent cell mediated cytotoxicity (ADCC). However, while trastuzumab can direct NK cells towards tumor cells and thereby promote tumor cell lysis, spheroid-forming tumor-initiating cells are largely spared. Consequently, populations of surviving cells showed greatly enhanced clonogenicity in vitro and tumorigenicity in vivo. Low HER2 levels and reduced expression of activating NK cell ligands provide likely explanations for the escape of these cells from HER2−directed NK cell-dependent therapies. Moreover, recent data show that unproductive interactions between immune cells and cancer cells can induce a process called “epithelial-to-mesenchymal transition” (EMT) which enables previously differentiated cancer cells to acquire stem cell-like properties as evidenced by a CD44highCD24low breast cancer stem cell signature and aldehyde dehydrogenase positivity. We thus investigated whether new HER2−specific antibodies could enhance NK-cell mediated target cell lysis or inhibit the induction of tumor stem cells.
The antibody pertuzumab also binds to the HER2−receptor. It inhibits homo- and heterodimerization of the HER2 receptor with other member of the HER family, in particular the dimerization of HER2/HER3 receptors. We were able to show that the combination of trastuzumab and pertuzumab leads to increased antibody-binding on breast cancer cells and breast cancer stem cells, resulting in enhanced ADCC. This correlates with the clinically observed synergy between trastuzumab and pertuzumab as observed for example in the Neosphere trial, a neoadjuvant study for HER2−positive breast cancer. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate which combines trastuzumab with the tubulin inhibitor maytansine. Interestingly, treatment with T-DM1 largely prevented the NK cell-dependent induction of the EMT markers Twist and Snail and the characteristic downregulation of E-cadherin. Thus, T-DM1 apparently interferes with EMT and may hence prevent the re-induction of the stem cell phenotype. In line with the presumed effect against cancer stem cells, T-DM1 significantly attenuated the clonogenic potential of FACS-sorted trastuzumab-unresponsive cancer stem cells. Accordingly, our data show that these new therapeutics may be more effective against cancer stem cells and thereby promise a more sustained treatment of HER2−positive breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-05.
P1-05-03: Relationship between Polycomb Repressive Complex EZH2/CBX7, Large Non-Coding RNA ANRIL and Stem Cells Biomarkers in Triple Negative Breast Carcinomas: Important Role in Carcinogenesis through an Epigenetic Silencing Process and New Clues for Targeted Therapies.
Authors: Meseure D , Vacher S , Trassard M , Drak-Alsibai K , Le Scodan R , Le Ray C , Regnier C , Lidereau R , Bieche I 
Published: June 2012

Abstract
Background: Epigenetic deregulation and carcinogenesis are intimately connected and gene silencing is a major consequence of epigenetic modifications. Polycomb group proteins (PcG) play important roles by inhibiting chromatin remodeling and transcription, silencing tumor suppressor genes, regulating stem cells and interconnecting with Wnt/beta-catenin, TGF-beta and Sonic-Hedgehog pathways. EZH2 is a transcriptional repressor and acts mainly as an oncogenic silencer gene involved in cell cycle regulation. Large non coding RNA are major regulators of oncogenic and oncosuppressive pathways at epigenetic, transcriptional and post-transcriptional levels. Recent studies have showed that (i) EZH2 overexpression is associated with cancer progression and aquisition of stem cell properties and (ii) disruption of ANRIL/CBX7 interactions repress the INK4b/ARF/INK4a locus. The aim of the study was to analyze PRC complexes, large non-coding RNA ANRIL and downstream signaling targets in triple negative breast carcinomas (TNC).
Design: By using real time quantitative RT-PCR in a series of 432 invasive breast ductal carcinomas (IDC), we quantified gene expression levels of the large non coding RNA ANRIL, PcG (EZH2, CBX7, SUZ12), stem cells markers (ALDH1, CD133, ASCL1) and oncosuppressor genes (p15, p16 and p19). Immunohistochemistry (IHC) was performed using EZH2, CBX7, ALDH1 and b-catenin Abs. We compared mRNA expression levels and IHC intensity score in TNC with non TNC and normal breast parenchyma.
Results: EZH2 overexpression was respectively found by RT-PCR and IHC in the TNC subgroup of IDC. We observed variable mRNA expression levels of SUZ12, CBX7, ANRIL, ALDH1, CD133, ASCL1, p15, p16, and p19. IHC showed EZH2 and CBX7 nuclear staining. Mutual positive correlations were found between EZH2, CBX7, ALDH1, ASCL1 and CCND1 (p&lt;10-5).
Conclusion: Polycomb EZH2/CBX7 and the large non coding RNA ANRIL are epigenetic transcriptional repressors overexpressed in the TNC subgroup of IDC. Their implication in the process of gene silencing (p16, p15, p19), activation of oncogenic pathways (Wnt, TGFb) and tumor stem cells self-renewal may explain several hallmarks of TNC and open new avenues to target this aggressive subgroup.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-05-03.
P1-05-04: Distinct Patterns of Promoter CpG Island Methylation of Breast Cancer Subtype Are Associated with Different Stem Cell Phenotype.
Authors: Park SY , Kwon HJ , Choi Y , Lee HE , Kim S-W , Kim JH , Kim IA , Jung N , Cho N-Y , Kang GH 
Published: June 2012

Abstract
Background: Although DNA methylation profiles in breast cancer have been connected to breast cancer molecular subtype, there have been no studies of the association of DNA methylation with stem cell phenotype. This study was designed to evaluate promoter CpG islands methylation of 15 genes with regard to breast cancer subtype and to investigate whether the patterns of CpG island methylation in each subtype are associated with cancer stem cell phenotype represented by CD44+/CD24- or ALDH1 expression.
Methods: We performed MethyLight analysis for the methylation status of 15 promoter CpG island loci involved in breast cancer progression (APC, DLEC1, GRIN2B, GSTP1, HOXA1, HOXA10, IGF2, MT1G, RARB, RASSF1A, RUNX3, SCGB3A1, SFRP1, SFRP4, and TMEFF2) and determined cancer stem cell phenotype by CD44/CD24 and ALDH1 immunohistochmeistry in 36 luminal A, 33 luminal B, 30 luminal-HER2, 40 HER2 enriched, and 40 basal-like subtypes of breast cancer.
Results: The number of CpG island loci methylated was significantly different among subtypes and it was highest in luminal-HER2 subtype and lowest in basal-like subtype. Methylation frequencies and levels in 12 out of the 15 genes were significantly different among all subtypes and basal-like subtype showed significantly lower methylation frequencies and levels in nine genes, compared to luminal A, luminal B, HER2 enriched, and luminal-HER2 subtypes. CD44+/CD24- or ALDH1+ putative stem cell populations were most enriched in basal-like subtype. The methylation of promoter CpG islands was significantly lower in CD44+/CD24-cell (+) tumors, compared to CD44+/CD24-cell (−) tumors, even within the basal-like subtype. ALDH1 (+) tumors also had significantly lower methylation, compared to ALDH1 (−) tumors.
Conclusions: Our findings showed that promoter CpG island methylation was significantly different according to breast cancer subtype and stem cell phenotype of tumor, suggesting that breast cancers have different methylation patterns according to molecular subtypes and it is associated with stem cell phenotypes of the tumor.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-05-04.
P1-05-06: Hypermethilation 14-3-3- Sigma Promoter as a Biomarker to Screening for Metastasis and Potencial Prognostic Factor in Breast Cancer Patients.
Authors: Martinez-Galan J , Torres-Torres B , González-Vicente A , Ruiz-Vozmediano J , Delgado-Pérez JR 
Published: June 2012

Abstract
Background: 14-3-3sigma is an epithelial marker whose expression is induced by DNA damage through a p53-dependent pathway. 14-3-3sigma functions sequesters cyclin B1-CDC2 complexes outside the nucleus and thereby contributes to a G2 arrest. Epigenetic silencing by CpG methylation, p53 inactivation, and proteasome-dependent proteolysis leads to loss of 14-3-3sigma and is often observed in precancerous lesions and likely to be causally linked to the onset of cancer
Objetive: To correlation methylation levels of promoter 14-3-3 sigma with association prognostic factors in breast cancer and their correlation with phenotype luminal.
Material and Methods: This is a prospective study we quantified methylation levels of promoter 14-3-3 sigma gene in 107 women with breast cancer and 108 control subjects by Real Time QMS-PCR SYBR green (methylation-specific PCR) and analyzed association with prognostics factor in breast cancer.
Results: Median age was 58 years (32-88); 69% were postmenopausal women. Nodal involvement N0; 63%,N1;30%,N2;7%), tumor size (T1;58%,T2;35%,T3;4%,T4;4%) and grade G1; 20%,G2;37%,G3;30%). Significant differences between breast cancer patients (pts) and healthy controls in relative serum levels of methylated gene promoters 14-3-3s (p=0.0047) were detected. Presence of methylated 14-3-3-s in serum of breast cancer patients was associated with T3-4 stage (OMS) (p&lt;0.05) and nodal positive status (p&lt; 0.05). With a median follow up 6 years we saw more probability of developing distance metastasis in patients with methylation 14-3-3 sigma (p&gt;0.05).
Conclusions: Hypermethylation of the 14-3-3 sigma promoter is an early and frequent event in breast neoplastic transformation, leading to the suggestion that silencing of 14-3-3 sigma may be an important event in tumor progression and particularly in breast carcinogenesis. This study identifies the presence of variations in global levels of methylation promoters genes in patients breast cancer with different phenotype classes and shows that these differences have clinical significance. Perhaps in the detection of CpG methylation of 14-3-3sigma may be used for diagnostic and prognostic purposes.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-05-06.
P1-06-10: Lobular Breast Cancer and NAC: Combined Results from the NKI and I-SPY 1 Trial.
Authors: Mukhtar RA , Lips E , Wesseling J , Livasy C , Yau C , Berry D , van't Veer L , Carey LA , Esserman LJ , Rodenhuis S , Hwang ES 
Published: June 2012

Abstract
Background
The benefits of neoadjuvant chemotherapy (NAC) in breast cancer are twofold: allowing breast conservation surgery, and assessment of response. Having pathologic complete response (pCR) predicts improved outcomes. Many have suggested that invasive lobular cancers (ILC) do not respond to NAC as well as invasive ductal cancers (IDC), and recommend against offering NAC in such cases. We previously investigated differences in the response to NAC in ILC and IDC in the I-SPY 1 Trial, and now present findings from a joint analysis with the Netherlands Cancer Institute (NKI).
Methods: We combined datasets comprising 676 patients (221 from I-SPY, 455 from NKI) enrolled in NAC trials. Eligible patients had palpable tumors ≥ 3 cm, and underwent serial biopsies, microarray analysis (Agilent 44K for I-SPY and Illumina 6v3 for NKI), and MRI imaging. ILC versus IDC histology was assigned by pathologic appearance, and ILCs were tested for e-cadherin expression and centrally reviewed by a breast pathologist at each site. We performed multivariate logistic regression analyses to assess differences in pCR. We compared intrinsic subtypes, prognostic gene signature expression, and MRI phenotypes.
Results: There were 75 ILC and 601 IDC cases. ILCs had lower risk features and were more likely hormone receptor + (Table 1) but there was substantial heterogeneity and many ILC had high risk features. There were fewer T2 (33% versus 48%) but more T3 tumors (59% versus 37%) among the ILCs. Nearly 10% of ILC cases had the basal intrinsic molecular subtype; 22% expressed the activated wound healing signature, and 56% had a high risk 70-gene prognostic signature. While pCR rate was lower in ILCs, adjustment for low risk features showed lobular histology was not an independent predictor of pCR. ILC was less likely to present as a solid mass. 85% of ILC were e-cadherin negative.

Conclusions: This combined analysis suggests that the decreased response to NAC in ILC is due to the association between ILC and low risk features. ILC in a clinically high risk setting has a higher proportion of high risk biology in spite of lobular histology. Lobular histology alone should not be used to exclude patients from NAC trials or treatment.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-10.
P1-06-12: Circulating Tumor Cells (CTC) Monitoring during Phase II Study with Lapatinib (L) and Capecitabine (C) in Patients with Brain Metastases from HER2−Positive (+) Metastatic Breast Cancer (MBC) before Whole Brain Radiotherapy (WBR): LANDSCAPE Study.
Authors: Pierga J-Y , Cropet C , Tresca P , Dalenc F , Romieu G , Campone M , Mahier Aït-Oukhatar C , Le Rhun E , Gonçalves A , Leheurteur M , Domont J , Gutierrez M , Curé H , Ferrero J-M , Labbe-Devilliers C , Bidard F-C , Bachelot T 
Published: June 2012

Abstract
Background: Decrease of CTC level during treatment in MBC has been reported as an independent prognostic and predictive factor of patients’ outcome. Monitoring CTC in addition to clinical response criteria is currently evaluated in early clinical trials in various cancer types. We sought to evaluate the clinical interest of peripheral blood CTC for patients included in the LANDSCAPE study which assessed the efficacy of upfront systemic treatment with L+C for newly diagnosed brain metastasis.
Methods: This analysis is a preplanned secondary endpoint of the LANDSCAPE study. Eligible pts had HER2+ MBC with BM not previously treated with WBR, C or L. Pts received L1250 mg/day and C2000 mg/m2/day, days 1–14, every 21 days. The primary endpoint was a centrally assessed CNS objective response (CNS-OR) defined as a ≥50% volumetric reduction of CNS lesions in the absence of increasing steroid use, progressive neurologic symptoms or progressive extra-CNS disease. CTC were detected in 7.5 ml of blood using the CellSearchSystem™, combining EpCAM immunomagnetic selection (IMS) followed by anti-cytokeratin (A45B/B3) fluorescently staining for CTC at baseline and at day (D) 21, before cycle 2.
Results: From 04/2009 to 08/2010, 45 pts were enrolled, 41 were evaluable for CTC at baseline and 38 at D21. Median age was 56 (range 35 to 79). PS was &gt;1 only in 2 pts. At baseline, 20/41 (48.8%) pts had ≥ 1CTC and 9 (22%) ≥ 5CTC (range 1–301, median 3). CTC were detected in pts with (18/37) or without disease outside SNC (2/6) (p=0.63). At a median follow-up of 10 months (range 2.9−16.5), median TTP was 6.0 months [95% CI 4.9; 7.4] vs. 4.3 [2.8; 5.9] months for pts without and with CTC at baseline respectively (p=0.14). After 21 days of treatment, a disappearance of CTC was observed in 11pts (31%). At D21, only 7 (18.4%) pts had ≥ 1CTC and 3 (8%) ≥ 5 CTC (p=0.006, D21 vs. baseline). In 43 evaluable pts, CNS-OR rate was 67% (95%CI 51–81), with a median time from inclusion to response of 1.8 month. Absence of CTC was not correlated with CNS-OR rate at baseline (17/21 (81%) vs. 11/19 (58%), NS). Strikingly, remaining positivity for CTC at D 21 (≥ 1CTC) was correlated with a poor response rate in CNS: 2/6 (33.3%) vs. 25/31 (80.6%) in pts with 0 CTC, p=0.03.
Conclusions: Early decrease (at D 21) in CTC level is correlated with a high response rate in newly diagnosed BM to L + C and underlines the predictive value of this blood marker in MBC pts even for brain metastasis. Longer follow-up is needed to assess its prognostic value under antiHER2 targeted therapy.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-12.
P1-06-15: A Genomic Predictor Developed from Breast Cancer Cell Lines Predicts Both Disease-Free Survival and Overall Survival in Breast Cancer Patients Treated with Doxorubicin and Cyclophosphamide: A Collaborative Project of the NSABP and Precision Therapeutics.
Authors: Shen K , Tang G , Kim C , Pogue-Geile K , Anderson SJ , Constantino JP , Bear HD , Song N , Tian C , Gabrin MJ , Zhang Y , Geyer CE , Wolmark N 
Published: June 2012

Abstract
Background: A cell line-derived multigene predictor of tumor response to doxorubicin + cyclophosphamide (MGP-AC) has been shown to predict the pathological complete response (pCR) in breast cancer patients from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-27. However, a cell line-derived MPG for doxorubicin + cyclophosphamide + docetaxel (MGP-ACT) was not predictive in patients from B-27. The purpose of this study was to further assess the performance of these predictors on disease-free survival (DFS) and overall survival (OS) in the same patient populations.
Methods: NSABP B-27 was a 3-arm trial of 2411 early-stage breast cancer patients randomized to receive 4 cycles of preoperative doxorubicin+cyclophosphamide (AC) or 4 cycles of AC followed by 4 cycles of docetaxel either pre-op (AC+T) or post-op (AC→T). MGPs for AC and ACT were developed based on the in vitro assay and microarray genomic profiles of 40 breast cancer cell lines. A higher MGP score indicates lower chemoresponse sensitivity.
Results: 322 patients with available microarray data were included for this analysis (103 treated with AC, 102 with AC+T, and 117 with AC→T). For patients treated with AC, a higher MGP-AC score was significantly associated with increased risk of disease progression (standardized hazard ratio [HR] [SD set to 1]=1.48, 95% confidence interval [CI]=1.02−2.15, p=0.043) or death (standardized HR=1.66, 95% CI=1.06−2.62, p=0.028) after adjusting for clinical covariates (ER status, clinical tumor size, lymph node status, and age). The addition of MGP-AC to the clinical model improves the accuracy in predicting five-year DFS: the area under the ROC curve improved from 63% to 72%. For patients treated with AC+T or AC→T, MGP-ACT was not predictive of either DFS (standardized HR=1.03, 95% CI=0.78−1.37, p=0.818) or OS (standardized HR=1.05, 95% CI=0.73−1.51, p=0.8).
Conclusions: A cell line-derived MGP for AC that was predictive of pCR was also predictive of DFS and OS in breast cancer patients treated with neoadjuvant AC. The MGP for ACT, which was not predictive for pCR, was not predictive of either DFS or OS in patients who received docetaxel after AC.
The B-27 study was funded by NCI PHS grants U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651, and U24-CA-114732, and received additional support from sanofi-aventis.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-15.
P1-07-04: Gene Expression Module Biomarkers To Stratify Multiple Clinical and Therapeutic Endpoints for Universal Breast Cancer Companion Diagnostic.
Authors: Rhodes D , Tomlins S , Williams P , Sadis S , Wyngaard P , Oades K , Chattopadhyay S , Wang Y , Monforte J , Lee B-I 
Published: June 2012

Abstract
Gene expression patterns are increasingly capable of stratifying patients based on prognosis and response to therapy. Given the limited availability of sample tissue, however, it is not feasible to run many tests, suggesting the need for a universal companion diagnostic assay that is informative with respect to multiple clinical and therapeutic endpoints. Key challenges are identification of appropriate gene expression biomarkers, translation of biomarkers to clinical assays, and development of reliable gene expression profiling of formalin-fixed clinical specimens. Here, we describe a meta-analysis approach that identifies novel biomarker modules that results in multiple clinical and therapeutic read-outs.
A co-expression meta-analysis of 5,339 breast tumors from 56 microarray datasets identified highly co-expressed sets of genes (modules) across multiple datasets. These module based biomarkers were tested for their ability to associate with prognostic and predictive targets in published datasets. In addition, each module was reduced from 10 - 1,000 genes to the top performing 2–3 genes based on the degree of co-expression across the meta-analysis and validation by quantitative PCR in an independent panel of FFPE tumor samples. This study demonstrates that a single 96 gene qPCR test utilizing multiple module biomarkers is not only capable of stratifying patients by standard histopathological parameters (ER, PR and Her2), but also stratifies by other diverse elements of the disease (cell lineage, dysregulated core biological functions, factors of cell growth, underlying genomic aberrations and the tumor microenvironment). Taken together, these biological variables represent the major biological diversity present within the breast cancer population. A series of retrospective analyses demonstrated that different single module and combinations of modules were capable of predicting a variety of clinical endpoints, including 5-year survival, neoadjuvant chemotherapy response in ER- patients and targeted therapy response in model systems.The molecular heterogeneity of breast cancer can be summarized by discrete gene expression modules that individually represent distinct biological pathways, and that collectively can be represented by as few as 96 genes. These breast cancer modules, together with outlier genes, allow for summation of the entire transcriptional program and provide a universal assay with broad application to companion diagnostics development.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-07-04.