bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-04-19: Neutralizing antibody to human GP88 (progranulin) restores sensitivity to tamoxifen and inhibits breast tumor growth in mouse xenografts
Authors: Serrero G , Dong J , Hayashi J 
Published: August 2014

Abstract
The 88 kDa glycoprotein GP88 (Progranulin, PCDGF, acrogranin) is the largest member of the granulin/epithelin family of growth modulators characterized by 7.5 cysteine-rich granulin/epithelin repeats. Our laboratory has demonstrated that GP88 represents an ideal therapeutic and diagnostic target in breast cancer. Our published studies have demonstrated that: 1) GP88 expression increases with tumorigenesis; 2) inhibition of GP88 expression by antisense transfection in MDA-MB-468 cells inhibited by 90% tumor formation in nude mice; 3) in ER+ breast cancer cells, GP88 stimulates proliferation and its overexpression confers estrogen independence and resistance to several anti-estrogens and aromatase inhibitor; 4) In Her-2 overexpressing breast tumors, GP88 stimulated Her-2 phosphorylation and conferred trastuzumab resistance; 5) GP88 is expressed in 80% invasive ductal carcinoma and 60% of ductal carcinoma whereas it is negative in lobular carcinoma, benign lesions and normal mammary epithelial cells; 6) pathological studies with 530 cases of ER+ invasive ductal carcinoma showed that GP88 tumor expression measured by immunohistochemistry (IHC) is a prognostic indicator of recurrence in early stage breast cancer patients; High GP88 tissue expression was associated with a 4-fold increase in risk of recurrence at 5 years; 7) GP88 is secreted and can be detected in the serum of breast cancer patients at an increased level when compared to healthy subjects. Based on these results, we developed a neutralizing anti-GP88 antibody AG1. AG1 was expressed in a high yield CHO cell line and formulated. AG1 inhibits GP88 biological effect (proliferation and migration) in a dose-dependent fashion in vitro. Here we will report the results of studies investigating the effect of AG1 on the tumor development of tamoxifen sensitive (MCF-7) and resistant (TamR) estrogen receptor positive breast cancer cells lines injected in nude mice. We show that AG1 alone (5mg/kg) inhibited tumor growth of MCF-7 cells injected into nude mice in a similar efficacy as tamoxifen. Interestingly, in tamoxifen resistant cells derived from MCF-7, the anti-GP88 antibody AG1 inhibited by more than 50% tumor formation of TamR cells in combination with tamoxifen, whereas tamoxifen only had no effect.
These data suggest that inhibiting GP88 provides a novel and alternative therapeutic pathway for the restoration of tamoxifen sensitivity in ER+ breast cancer.
This works is supported by grant 2R44CA124179 from the National Cancer Institute and 02–2010-010 from the Avon Foundation for Women.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-19.
Abstract P6-04-30: COUP-TFII suppresses NFκB activation in endocrine-resistant breast cancer cells
Authors: Litchfield LM , Klinge CM 
Published: August 2014

Abstract
COUP-TFII is an orphan nuclear receptor that functions as either a transcriptional activator or repressor. We previously reported that COUP-TFII expression is reduced in endocrine-resistant LCC9 breast cancer cells and that overexpression of COUP-TFII restored the ability of the antiestrogen tamoxifen to inhibit cell proliferation. An increase in NFκB activity and p65/RELA expression has been reported in endocrine-resistant breast cancer cells. Because NFκB activation results in increased expression of anti-apoptotic and pro-proliferative genes, increased NFκB signaling promotes the survival of cancer cells. The goal of the current study was to further elucidate the mechanism by which COUP-TFII enables cells to maintain endocrine sensitivity and to determine if COUP-TFII can modulate NFκB activity in tamoxifen-resistant breast cancer cells. To examine whether COUP-TFII can suppress NFκB activity, MCF-7 (tamoxifen-sensitive, TAM-S) and LCC9 (tamoxifen-resistant, TAM-R) breast cancer cells were transfected with a NFκB luciferase reporter and treated with TNFα to activate NFκB. NFκB activity was elevated in LCC9 TAM-R cells and co-transfection with COUP-TFII reduced NFκB activity. COUP-TFII overexpression led to a statistically significant reduction in the expression of NFκB subunits RELA, RELB, NFKB1, and REL in LCC9 cells. Significantly reduced expression of NFκB target genes IL6, ICAM1, TNFAIP3, and CCL2 was also evident upon COUP-TFII overexpression, reflecting the suppression of the NFκB pathway by COUP-TFII. Inhibition of NFκB activation by COUP-TFII also led to a reduction in cell viability in TAM-R cells in response to tamoxifen treatment. Together these data indicate a novel role for COUP-TFII in suppression of NFκB activity which may explain the ability of COUP-TFII to promote tamoxifen-sensitivity. COUP-TFII may be both a useful biomarker to predict tamoxifen-sensitivity as well as a target to restore endocrine sensitivity to resistant cells.
Supported by NIEHS T32 ES011564 predoctoral fellowship to L.M.L. and Susan G. Komen for the Cure grant KG080365 to C.M.K.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-30.
Abstract P6-05-09: Unravelling the global effect of estrogen on breast cancer cell proteome using quantitative proteomics.
Authors: Pavlou MP , Drabovich AP , Dimitromanolakis A , Diamandis EP 
Published: August 2014

Abstract
Estrogens exert their function through genomic and non-genomic pathways mediated mainly by estrogen receptors. Estrogen signalling is highly complex and once activated initiates cancer cell proliferation and survival, playing a pivotal role in breast cancer development and progression. The identification of estrogen regulated genes is the first step towards elucidating the mechanisms of estrogen function. Although numerous studies have investigated the effect of estradiol at the mRNA level, assessment of global changes at the protein level has been limited mainly due to technological limitations.
Here, we present the most extensive proteomic study in the quest of proteins whose expression is regulated or associated with estradiol action. To facilitate accurate quantification of proteins, we first developed and optimized a proteomic protocol for cell lysis and sample preparation, based on a mass spectrometry-compatible detergent. Following our protocol coupled to stable isotope labelling with amino acids in cell culture (SILAC) of MCF-7 breast cancer cells, we quantified approximately 4,000 proteins and identified 153 proteins differentially expressed upon estradiol stimulation. Notably, known estrogen regulated proteins such as trefoil 1(TFF1) and progesterone receptor (PGR) showed a four- and three-fold increase respectively, at 48 hours after estradiol stimulation. Forty eight of 153 differentially expressed proteins have been found to contain estrogen receptor elements (EREs) indicating direct regulation by estradiol. Protein-protein network analysis (STRING) revealed an extensive protein network related to cell proliferation. Differential expression of proteins was verified in three estrogen receptor positive breast cancer cell lines (MCF-7, HCC-1428, BT-483) using a targeted mass spectrometry-based quantitative approach; selected reaction monitoring (SRM). A multiplex SRM assay was developed for the simultaneous quantification of 56 proteins. The same assay was utilized to study the kinetics of these proteins in time and in presence of inhibitors of estrogen receptor facilitating the distinction between direct and indirect protein targets.
To our knowledge, such an extensive network of estrogen-regulated genes has never been previously studied at the protein level. Interestingly, numerous differentially expressed proteins identified in the present study have not been connected to estrogen signalling or breast cancer before. The role of these proteins in breast carcinogenesis and their potential as therapeutic targets warrants further investigation.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-09.
Abstract P6-07-05: Prognosis of 368 women with primary breast cancer during pregnancy: results from an international collaborative trial
Authors: Amant F , von Minckwitz G , Han SN , Bontenbal M , Ring A , Giermek J , Fehm T , Wildiers H , Linn SC , Schlehe B , Neven P , Westenend PJ , Müller V , Van Calsteren K , Rack B , Nekljudova V , Harbeck N , Lenhard M , Witteveen PO , Kaufmann M , Van Calster B , Loibl S 
Published: August 2014

Abstract
Objective: We aimed to add to the limited outcome data on breast cancer during pregnancy (BCP), and compared disease-free survival (DFS), and overall survival (OS) between patients with BCP and breast cancer not diagnosed during pregnancy, adjusted for known prognostic factors.
Methods: We analyzed a pro- and retrospectively compiled multi-centric registry of BCP patients (www.cancerinpregnancy.org and GBG/BIG 0203). Outcome was compared to a control group of patients who did not have associated pregnancies. The main analysis is a Cox proportional hazards regression of disease free survival (DFS) and overall survival (OS) on exposure (pregnant or not). The analysis was weighted by propensity score matching to correct for any bias that may have been associated with differences in baseline characteristics, with the following set of covariates: age, stage, grade, hormone receptor status, HER2 status, histology, type of chemotherapy and trastuzumab. Sensitivity analysis was also performed on age only, and also on chemotherapy only.
Results: From April 2003-December 2011, 447 women with BCP were registered, 368 women with BCP were eligible for this analysis. The control group consisited of 2739 women (ratio 1:7.44).

Median age was 33 years (interquartile range 30–36) for the cases and 41 years (interquartile range 37–43) for the controls. Median follow-up was 57 months. There were no statistically significant differences noted for DFS and OS studied after propensity-score matching, and sensitivity analysis.

Conclusion: Patients diagnosed with breast cancer during pregnancy do not have a worse prognosis compared to patients who are not pregnant after matching for prognostic factors and treatment. This information is important when BCP patients are counseled regarding prognosis and adds to the possibility of treatment during pregnancy.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-05.
Abstract P6-07-13: Local relapse and survival
Authors: Harland R , Prathap P , Lionaki A , Mahmood N 
Published: August 2014

Abstract
Aim: Local recurrence may precede distant relapse and death. Many factors which predict local recurrence also predict death. Few studies have investigated the contribution of local recurrence to mortality independent of prior prognostic factors such as nodal status. We wished to estimate the extent to which overall survival is affected specifically by local recurrence.
Methods: 114 of of 2945 patients aged 19 to 94 years (mean 58.3) who had either mastectomy or breast conservation for breast cancer between 1991 and 2011 subsequently suffered an ipsilateral local recurrence. We matched, with one exception (due to extreme young age), each patient who had a local recurrence with 2 controls matched for calendar year of presentation, age, nodal status, grade, and tumour size. A Cox regression analysis of survival from the first therapeutic operation was done on the case matched subset with local recurrence coded dichotomously and age coded continuously as the absolute deviation from the population mean (as both young and old age affect survival adversely) as predictors. To confirm independence of the effect of local recurrence on the hazard of death a further Cox regression analysis of survival as above was done for the whole series with local recurrence, Grade 3, &gt;3 nodes involved, tumour diameter &gt;40mm, coded dichotomously, and age coded as above as independent variables.
Results: The results of the analyses are given in the table below.

The estimate of hazard of death associated with local recurrence was similar in both analyses suggesting minimal confounding effect. As expected large tumour size, high grade and heavy nodal involvement predicted survival independently.
Conclusion: Local recurrence was associated with only a modest increase of about 50% in the hazard of death independent of tumour stage, size and grade which remained the most significant predictors within this model. Extremes of age were associated with increasing hazard of death and should be similarly coded when analysing unadjusted survival.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-13.
Abstract P6-07-19: Prognostic relevance of PR and detection mode in Luminal Her-2 negative breast cancer
Authors: Brouckaert O , Van Calster B , Paridaens R , Wildiers H , Van Limbergen E , Weltens C , Christiaens M-R , Neven P ,   Multidisciplinary Breast Centre
Published: August 2014

Abstract
Introduction: Although known to hold prognostic value, PR status is not used to discriminate luminal A from luminal B HER2 negative breast cancers. We will here assess whether PR (and also detection mode) is an independent prognostic variable in luminal HER2 negative breast cancer and whether the prognostic value of PR is grade dependent.
Patients and methods: Primary operable breast cancer patients diagnosed between 1/1/2000 and 31/12/2009 treated in UZ Leuven were retrieved from the prospectively managed database (n = 4318). Her-2 status was missing in 93 and ER/PR in 2 patients. Of the remaining patients, 3330 were luminal (ER and/or PR positive) HER2 negative (full cohort details: Brouckaert O., et al. Ann Oncol. 2012 Apr 6). Missing values were observed in 137 patients (4.1%), and these were imputed using ‘multivariate imputation by chained equations’. A competing risks proportional hazards model was used for multivariable analysis (includes age, size, grade, screening, palpability, nodal status, histology, type of surgery, radiotherapy, endocrine and chemotherapy) of distant metastasis free interval (DMFI) and breast cancer specific survival (BCSS). We used a predefined set of predictors, investigated non-linearity of the predictor effects, checked the proportional hazards assumption, and tested for interactions with grade.
Results: Median follow-up was 76 months and 5-year survival probability 93%. PR is an independent prognostic variable but this is grade dependent for DMFI, but not for BCSS (interaction p = 0.15), although PR positivity was mainly protective for grade 3 breast cancers again (table 1). Palpability is a strong prognostic variable for DMFI and BCSS and was strongly correlated with screen detection (yes/no) and here, we found no evidence of grade dependency.

Conclusion: PR status and palpability may further refine prognosis of patients with luminal HER2 negative breast cancers. For PR, prognostic value is grade dependent, but for palpability, this is grade independent.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-19.
Abstract P6-07-24: Prognostic Tools in Early Breast Cancer: Predicting benefit of adjuvant chemotherapy
Authors: Parkes EE , Davidson C , James CR , Hanna GG 
Published: August 2014

Abstract
Introduction: Adjuvant chemotherapy (CT) in early breast cancer reduces the risk of mortality. However, absolute reductions in mortality can be small. For patient with low risk disease, prognostic tools such as ‘Adjuvant! Online’ and ‘Predict’ can be used to estimate the benefit of adjuvant chemotherapy. We compare the survival gains estimated using ‘Adjuvant! Online’ and ‘Predict’ in routine clinical practice, assessing the characteristics of patients in which ‘Adjuvant! Online’ and ‘Predict’ disagree.
Methods: In a retrospective study using the hospital electronic database, the clinical and pathological details of all patients with early breast cancer referred for adjuvant therapy at the Northern Ireland Cancer Centre in a 3 month period in 2011 were collected and were entered in to ‘Adjuvant! Online’ and ‘Predict’ to assess percentage benefit (absolute reduction in mortality at 10 years) from CT. We categorised patients into three prognostic groups: those where risk from CT outweighs benefit (&lt;2% predicted benefit), marginal benefit (2 to 5%) and significant benefit from CT (&gt;5%) We excluded patients with metastatic disease at presentation, DCIS, a second primary breast cancer or receiving neo-adjuvant treatment.
Results: Of the 250 patients identified, 61 (24.4%) fell in to different prognostic groups depending on whether ‘Adjuvant! Online’ or ‘Predict’ was used to calculate benefit from CT. In those in whom there was disagreement, ‘Adjuvant! Online’ suggested marginal or significant benefit in 75.4% of patients, compared to 55.7% using ‘Predict’. Nine patients had “major” comorbidities, which is weighted only in ‘Adjuvant! Online’, and were excluded in subsequent analysis. Of those without major comorbidities, ‘Adjuvant! Online’ offered at least 2% benefit in 85% of cases, and ‘Predict’ in only 58.3%. The majority (93.3%) of cases were ER positive, and node negative (85.0%). This difference was notable in women aged 65 or less, with 86.2% with &gt;2% benefit using ‘Adjuvant! Online’, compared to 55.1% using ‘Predict’. ‘Adjuvant! Online’ estimates of benefit were on average 3.7% higher for this age group. HER2 status had little impact, with similar recommendations using either ‘Adjuvant! Online’ or ‘Predict’.
Conclusions: This study highlights lack of concordance between two available online prognostic tools, notably in ER positive, node negative patients. For patients with a marginal benefit from adjuvant chemotherapy, care must be used when making adjuvant treatment decisions as other prognostic tools may be of help in this group of patients.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-24.
Abstract P6-07-28: Assessment of T stage in the multiple breast carcinomas
Authors: Gong G , Jo J-H , Lee HJ , Kang J 
Published: August 2014

Abstract
Background: Tumor size is an important predictor of nodal metastasis, recurrence, distant metastasis in invasive breast carcinomas. T stage assignment of the multiple simultaneous ipsilateral breast carcinomas is based on the largest tumor with the suffix “(m)” to indicate multiplicity in the AJCC staging, and sum of the sizes should not be used. The aim of this study is to compare current AJCC staging and two test models using the aggregate of all tumor foci and the aggregate of all tumor volume in the single and multiple breast carcinomas.
Methods: We reviewed original pathologic reports of 1145 consecutive patients with invasive ductal carcinoma, 2003–2004. 131 (11.4%) patients had multiple masses. Three factors were used to compare T stages; (1) the greatest dimension of the largest invasive component (T), (2) the aggregate of all tumor foci (TA), and (3) the aggregate of all tumor volume (TV). T stage follows AJCC (7th ed, 2010) system. TA and TV were categorized as followings: TA1 &lt; 2cm, 2cm ≤ TA2 &lt; 5cm and TA3 ≥ 5cm; TV1 &lt; 8cm³ (average diameter &lt; 2cm), 8 cm³ ≤ TV2 &lt; 125cm³ and TV3 ≥ 125cm³ (average diameter ≥ 5cm). Clinicopathologic parameters were analyzed according to T stage.
Results: Axillary lymph node metastasis was more common in the cases with multiple masses (64/131, 48.9%) than single mass (397/1014, 39.2%) and the number of the metastatic lymph node was also higher in multiple cases. Multiple breast carcinomas tended to show frequent recurrence, and disease specific death compared with the single cases in the same stage. (p &lt; 0.05) Among 606 cases of T1, 34 cases were reclassified to TA2 and in 487 cases of the T2, 23 cases were reclassified to TA3. TV also showed reclassification of the cases. Multiplicity, T stage, TA stage, and TV stage were significant factors for nodal positivity in the univariate analysis (p &lt; 0.05). Nodal positivity was remained in the multivariate analysis for recurrence and disease specific death, but the other factors were not significant for nodal involvement, recurrence and disease specific death.
Conclusion: Multiple breast carcinomas has adverse patients' outcome than single carcinoma with same T stage of AJCC system and a better staging method is required to cover multiple carcinomas.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-28.
Abstract P6-07-30: The clinical significance of pathologic complete response using different definitions after neoadjuvant chemotherapy in HER2 positive breast cancer patients according to hormonal receptor status.
Authors: Tanioka M , Hirokaga K , Kitao A , Matsumoto K , Yoshida S , Miki M , Maekawa Y , Takao S , Negoro S 
Published: August 2014

Abstract
Background: For patients (pts) with HER2 positive (HER2+) breast cancer, the achievement of pathological complete response (pCR) after neoadjuvant chemotherapy is regarded as a surrogate endpoint of prognosis, however, the exact definition of pCR and its prognostic impact on survival in HER2+ breast cancer subtypes when stratified by hormonal receptor (HR) status is uncertain.
Methods: We retrospectively investigated 163 HER2+ pts who received neoadjuvant chemotherapy in Hyogo Cancer Center between 2003 and 2010. HR+ was defined as estrogen or progesterone receptor positive. pCR at surgery was defined as no evidence of invasive and noninvasive residual in the breast or axillary nodes (ypT0 ypN0), no evidence of invasive residual in the breast or axillary nodes; noninvasive breast residuals allowed (ypT0/is ypN0), or no evidence of invasive residual in the breast; noninvasive breast residuals and infiltrated lymph nodes allowed (ypT0/is ypN0/+). Logistic regression analysis and logrank test were performed to identify HR status as a predictor of pCR and its prognostic significance on recurrence-free survival (RFS).
Results: The median age at diagnosis was 55 years (range, 25–84) and the median follow-up period was 61 months (range, 15–104). Stage I, IIA, IIB, III were 4, 57, 56, 46 pts, HER2+HR+ and HER2+HR- were 89 and 74 pts, respectively. The rates of pts receiving anthracycline, taxane and trastuzumab were 66, 82 and 51%, respectively. After surgery, 98% of HER2+HR+ pts received hormonal therapy. Five-year RFS rates were significantly higher in HER2+HR- pts with pCR compared to non-pCR, however, which were similar in HER2+HR+ pts with pCR compared to non-pCR regardless of the pCR definitions.

In logistic regression analysis, significantly fewer HER2+HR+ pts achieved pCR compared to HER2+HR- pts regardless of the pCR definitions.

Conclusions: HER2+HR+ breast cancer pts had lower achievement rate of pCR, which was less prognostic compared to that in HER2+HR- pts regardless of pCR definitions. pCR is a suitable surrogate end point for HER2+HR- pts but not for HER2+HR+ pts in clinical trial settings.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-30.