bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-06-53: Ki67 labelling index (Ki67LI) can subdivide homogeneous HER2 negative luminal grading groups (HNL-GG) in distinct biological entities
Authors: Ferro A , Russo LM , Eccher C , Triolo R , Barbareschi M , Caldara A , Dipasquale M , Galligioni E 
Published: August 2014

Abstract
Background: Several studies have emphasized Ki67LI biologic and prognostic value and its potential application of its assessment in routine practice, particularly to define prognostic subgroups of luminal/hormone receptor-positive (HR+) tumors.
Methods: Ki67LI was identified by immunohistochemical staining in 3760 EBC pts treated from 1995 to 2008. Median age was 61 y. The relationship with clinic-pathological parameters and the prognostic significance of KI67LI were investigated in all EBCs and in HER2 negative luminal (2380 HNL) cases stratified on homogeneous grading (594 G1, 1282 G2, 504 G3).
Results: Median Ki67LI values were 22% in all cases, 20% in HNL and 10, 20 and 35% in different HNL grading group (HNL-GG).
Ki67LI &gt; 22% (1873 pts) was significantly (p&lt;0.001) associated with younger age, ductal type, greater size, positive N, poor G, absent or low ER /PR expression, positive HER-2, triple negative subtypes.
Local and Distant Relapses were 138 (7.3%) and 355 (18.9%) in &lt; or &gt; 22% Ki67LI respectively. Median time to first event was 31.7 ms in &gt; 22% vs 50.1 ms in &lt; 22% Ki67. At median f-up of 77 months EFS and OS were 91.9 and 92.1% in &lt; 22% vs 78.9% and 81% in &gt; 22% Ki67 respectively (p &lt;0.001).
Prognosis in term of DFS and OS was consistently worse for &gt; 22% compared to &lt; 22% Ki 67 in all clinical-pathological subsets, except in negative ER group. In multivariate analysis, KI 67mantained an independent prognostic significance for DFS and OS.
In HNL, EFS and OS were 93.7 and 92% in &lt; 20% vs 81.7 and 83.3% in &gt;20% Ki67(p &lt;0.001). Using median ki67LI value for different homogenous HNL-GG as cutoffs, we stratified these populations in low and high risk. The results are shown in the following table.
Stratification in high and low risk subgroups of homogeneous HNL-GGSubgroupsEFSpOSpG1 high91.7%0.04392.7%0.114G1 low96.0% 96.0% G2 high84.2%&lt;0.00187.5%0.012G2 low93.7% 90.6% G3 high70.9%0.05376.4%0.036G3 low83.2% 80.7%
Conclusions: Our study confirms prognostic value of Ki67LI in EBC, associated with other clinical-pathological characteristics. Cutoffs are different into HNL-GG. They can cathegorize at least two biological entities in every grading group providing additional prognostic information in planning therapies and outcome prediction.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-53.
Abstract P6-07-11: Health economic impact of breast cancer index (BCI) for late disease management in patients with estrogen receptor-positive, node-negative breast cancer
Authors: Gustavsen G , Schroeder BE , Kennedy P , Pothier K , Erlander MG , Schnabel CA 
Published: August 2014

Abstract
Background
Several recent randomized, prospective clinical trials (MA.17, ATLAS, aTTom) have demonstrated the clinical benefit of extending endocrine therapy beyond 5 years to address the persistent risk of recurrence in patients with ER+ breast cancer. Breast Cancer Index (BCI) is a gene expression-based test that predicts overall (10y) risk of recurrence in patients with ER+, LN- breast cancer, and also informs late (post-5 year) disease management by providing information on risk of late (≥5y) recurrence, and likelihood of benefit from extended (≥5y) endocrine therapy. Previously, BCI was shown to be cost saving across a 10-year disease horizon. The current study specifically assessed the health economic benefit of BCI for late disease management, evaluating the impact of identifying patients at risk of late recurrence and those that may benefit from extended endocrine therapy.
Methods
A fact-based economic model was developed which projected the cost and effectiveness of BCI from a US third-party payer perspective in a hypothetical population of patients with ER+, LN- breast cancer who are disease free at 5 years post-diagnosis compared to standard clinical practice. Patients flowed through the model based on patterns of care and BCI data. Costs associated with endocrine therapy, toxicity, follow-up, and recurrence were modeled over 5 yrs. Model inputs were based primarily on published literature, and supplemented by interviews with disease experts and payers. Sensitivity analyses were performed around key inputs to estimate effects on the model.
Results
Use of BCI is projected to be cost saving in this population of patients that are disease-free at 5 years post-diagnosis, with a net cost savings of $691 per patient tested after accounting for BCI cost. Gross cost savings were projected to be achieved through reduced recurrence in patients receiving extended endocrine therapy based on BCI ($4,102), and reduced recurrence in previously non-compliant patients ($39). BCI was cost saving for both pre- and post-menopausal women. Sensitivity analyses demonstrated that results were most sensitive to current use of extended endocrine therapy in postmenopausal patients, future use of extended endocrine therapy in BCI (H/I) high patients, and the percentage of patients characterized as BCI (H/I) high.
Conclusions
BCI is projected to be cost saving in a population of ER+, LN-, breast cancer patients who are recurrence free at 5 years post-diagnosis. Cost savings are achieved through projected impact on extended endocrine therapy use and endocrine therapy compliance, and provide additional cost savings beyond impact on chemotherapy utilization. These findings require validation in additional cohorts, including studies of real-world clinical practice.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-07-11.
Abstract P6-08-06: Sexual function, sexual activity and quality of life in women with breast cancer
Authors: Beutel B , Schrof I , Rita H , Lehmann K , Kullmann V , Alexander T , Herbert S , Andreas DB 
Published: August 2014

Abstract
Background: Breast cancer (BC) is generally assumed to have an impact on sexual function and activity. Although there are several studies addressing the issue, case control studies are currently limited.
Methods: We performed a cross-sectional investigation of sexual function and activity utilizing the sexual activity questionnaire, the female sexual function index, and parts of the EORTC QLQ C30. Patients with breast cancer (BC) were compared with a control group (C) of non-cancer patients. Inclusion of BC was only allowed if treatment was completed ≥ 12 months previously and patients were disease-free. This study was approved by the ethical committee of the Landesärztekammer Hessen. All consecutive patients with breast cancer who were treated at our hospital were prospectively documented in a clinical tumor registry since 2001. All patients’ records are updated annually. The control sample without any oncologic disease of 392 age-matched females was recruited in the Department of Prosthodontics, University Hospital Mainz.
Results: Between December 2009 and May 2010 the questionnaires were sent out to 790 women (398 x BC and 392 x C), 21.6% of which responded. Response rates in both groups were equivalent (84 patients with BC [21.2%] and 87 control subjects [22.2%]). Median age was 57 years (C) and 62 years (BC), respectively (p = 0.005). 51.5% (C) and 60% (BC) were not sexually active, mainly owing to lack of a partner (39%) or lack of interest (21%) in controls and lack of interest (48%, p&lt;0.05), self-reported physical problems (34%, p&lt;0.05), and physical problems of the partner (22%, p&lt;0.05) in breast cancer patients. There were significant differences between both groups in the SAQ discomfort score (p&lt;0.05). We did not observe significant differences in quality of life or other scores regarding sexuality.
Conclusions: About half of the women in both groups were not sexually active. However, reasons for non-activity differ. Quality of sexuality tends to be impaired in BC patients, but this seems not to influence quality of life. A shift of priority caused by substantial anxiety regarding cancer specific survival might explain our findings.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-08-06.
Abstract P6-09-05: Neem leaf extract, rich in nimbolide and azadirachtin targets radiation-induced stemness in surviving breast cancer cells
Authors: Pandian V , Natarajan M , Aravindan S , Herman TS , Aravindan N 
Published: August 2014

Abstract
Recently, we have shown that the neem leaf extract (NLE) rich in Nimbolide and Azadirachtin exerted radiosensitization and alleviates tumor progression in varied solid tumor models. Accordingly, in this study, we investigated its potential in the regulation of radiation (IR)-induced stemness in surviving breast cancer (BCa) cells. Human breast adenocarcinoma (MCF-7) cells either mock-irradiated or exposed to IR (2Gy) with or without NLE (1, 10 or 100μg) pre-treatment (for 3h) and analyzed at 3h or 24h post-IR. Transcriptional alterations of 93 molecules that drive EMT, CSCs self-renewal capacity and pluripotency maintenance were analyzed using QPCR profiling. NANOG, SOX2, ABCG2, N-cadherin, E-cadherin and GSK3β expression was examined by immunoblotting. Radiation profoundly increased 67 stem-cell related molecules in surviving BCa cells. NLE exerted a dose-dependent (1μg, 23; 10μg, 51; 100μg, 64 genes) inhibition of IR-induced stem-cell related molecules. Second-phase observations at 24h post-IR revealed no recovery of NLE-inhibited transcription with complete inhibition of 12, 66 and 64 genes after 1, 10 and 100μg. Gene comparison analysis revealed both ‘dose-independent’ (20genes at 3h and 12genes at 24h) and ‘time-independent’ (6, 50 and 61 genes at 1μg, 10μg and 100μg respectively) inhibition. Interestingly, six genes (BMP4, CDH1, EGF3, FOXA2, GSK3β and HDAC2) showed both ‘time-and-dose-independent’ inhibition. Coherently, immunoblotting revealed a consistent regulation of IR-induced NANOG, SOX2, ABCG2, N-cadherin in the surviving BCa cells. Together these data demonstrate that NLE targets IR-induced stemness in surviving BCa cells and may thus serve as a potential “deliverable” to negate breast cancer relapse and progression.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-09-05.
Abstract PD4-1: Comparison of mutations and protein expression in potentially actionable targets in 5500 triple negative vs. non-triple negative breast cancers
Authors: O'Shaughnessy JA , Gatalica Z , Kimbrough JM , Millis SZ 
Published: August 2014

Abstract
Introduction
Triple negative breast cancer is a heterogeneous disease with no established targeted treatment options for patients with metastatic disease.
Methods
A cohort of 5500 patient samples was evaluated for differences and similarities in gene mutation (Sanger or Illumina Truseq), protein expression (immunohistochemistry), and/or amplification/rearrangement (CISH or FISH) between triple negative and non-triple negative breast cancers, with 16% of those patients identified as triple negative by IHC testing.
Results
PIK3CA and P53 gene mutations, PIK3CA, TOP2A, and EGFR amplification (measured as ≥ 4 copies in 40% or more tumor cells by FISH), and AR, EGFR, SPARC, and TS protein expression were shown to differ between the triple negative and non-triple negative breast cancer patients. The rate of mutation of the P53 tumor suppressor gene, measured by sequencing was twice as high in TNBC patients as in non-TNBC patients (60% versus 30%), while PIK3CA was mutated in half as many TNBC patients (12% versus 31% of non-TNBC patients). Amplification of Her2, PIK3CA, cMYC, and TOP2A was significantly greater in the non-TNBC patient population, while amplification of EGFR was significantly higher in the TNBC patient population (24% versus 13% of non-TNBC patients). Androgen receptor was expressed in 56% of the non-TNBC cohort but in only 15% of the TNBC cohort.
Conclusions
The gene mutation and protein expression differences in the triple negative subset of breast cancer patients, such as EGFR amplification, SPARC protein expression and P53 gene mutation, could inform new therapeutic possibilities for these difficult to treat, often more aggressive cancers.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD4-1.
Abstract PD5-3: Anti-metastatic activity, chemotherapeutic enhancement and therapeutic potential of targeting Hsp90 with ganetespib in triple negative breast cancer
Authors: Proia DA , Zhang C , Sequeira M , Jimenez J-P , He S , Nagai M , Acquaviva JL , Smith DL , Sang J , El-Hariry I 
Published: August 2014

Abstract
Background: While the incidence of triple negative breast cancer (TNBC) is only 10-20%, these tumors show a disproportionate mortality for breast cancer patients. Due to a lack of effective molecular targets in this disease, therapeutic options are largely limited to systemic chemotherapeutic approaches which have shown disappointing efficacy in the metastatic setting. Here we undertook a comprehensive evaluation of the activity of the drug candidate, ganetespib, a potent inhibitor of heat shock protein 90 (Hsp90), in this malignancy.
Methods: The sensitivity of TNBC cells to ganetespib was determined in viability assays using a panel of tumor lines. The effects of ganetespib exposure on client proteins and their effector pathways were examined by Western blot and reverse phase protein array analysis. The anti-metastatic activity of ganetespib was evaluated using a 4T1 metastasis model. Combinatorial drug analyses were performed with chemotherapeutic agents. DNA damage and cell cycle disruption were assessed using the comet assay, Western blotting and fluorescence microscopy. The in vivo efficacy of the compound, both as a single agent and in combination, was established using MDA-MB-231 xenograft models. Computed tomography scans were obtained for a metastatic TNBC patient undergoing ganetespib treatment.
Results: Ganetespib reduced cell viability in TNBC cell lines with low nanomolar potency. Ganetespib treatment induced robust destabilization of multiple client proteins and oncogenic signaling pathways and suppressed lung metastasis in the experimental model. Ganetespib potentiated the cytotoxic activity of doxorubicin via enhanced DNA damage and mitotic arrest, conferring superior efficacy to the doxorubicin + cyclophosphamide (AC) regimen in MDA-MB-231 xenograft models. Ganetespib also promoted mitotic catastrophe and apoptosis in combination with taxanes in vitro, and these effects translated to significantly improved combinatorial activity in vivo. Marked tumor shrinkage of metastatic lung lesions was seen in the patient while on ganetespib monotherapy.
Conclusion: The preclinical activity profile and clinical evidence of tumor regression suggest that ganetespib offers considerable promise as a new therapeutic candidate to target TNBC. In particular, the capacity of ganetespib to potentiate the activity of standard of care chemotherapeutics provides a rationale for the exploration of this agent in novel combinatorial treatment strategies for this disease.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-3.
Abstract PD6-1: Tumor spheres growing from peripherally circulating tumor cells exhibit stem cell features
Authors: Pachmann K , Zimon D , Pizon M , Pachmann U 
Published: August 2014

Abstract
Background: Among the cells that are disseminated from a malignant tumor only very few are capable to resettle in distant organs and grow into life-threatening metastases. Therefore, the question arises how and whether such cells which have the potential to grow into metastases can be detected. It has been shown that a subpopulation of cells from breast cancer tissue can form so-called mammospheres with stem cell features. Here we show that such tumor spheres can also be grown from peripherally circulating tumor cells from breast cancer patients in different stages of disease
Materials and Methods: Using a nondissipative approach with only one enrichment step of red blood cell lysis, the cells from the pellet, containing the white blood cells together with the putative tumor cells were cultured under conditions favoring the growth of epithelial cells. At 7, 14 and 21days the cell cultures were inspected for the appearance of spheroids staining with anti-EpCAM, anti-CD24 and anti-CD44 antibody and.expressing ALDH1.
Results: Peripherally circulating cells from patients with malignant tumors in different stages of disease were analyzed for the presence of circulating epithelial tumor suspect cells and the frequencies of tumorspheres. Tumorspheres could so far be grown from 79% of 36 patients in whom more than 1700/ml epithelial tumor suspect cells were detected. Numbers of tumorspheres varied from 1 to 29 /ml and correlated with the aggressiveness of the tumor. Surprsingly the numbers were highest in patients after surgery who had not yet received any systemic therapy. The size of the spheres increased from day 7 to day 21. The spheres were negative for CD24 and positive for CD44. They highly express ALDH1 and thus exhibite typical features of stem cells.
Conclusion: Here, we demonstrate that the circulating tumor cells, detected in our approach contain a subpopulation with stem cell-like properties capable of growing into tumorspheres. The frequency and growth potential of cells capable of forming spheres seems to be dependent from the properties of the primary tumor. The possibility to grow tumorspheres from peripherally circulating tumor cells may open up a new field, where the relevant cells with stem cell properties from individual patients can now be specifically analysed further for genetic endowment, transcriptional activity, heterogeneity and stem cell markers.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD6-1.
Abstract S2-06: Extracellular matrix stiffness modulates tissue inflammation to promote breast tumor aggression
Authors: Acerbi I , Hwang S , Munson J , Au A , Zheng S , Yu H , Mouw J , Lakins J , Swartz M , Shi Q , Liphardt J , Ruffell B , Coussen LM , Yunn-Yi C , Weaver VM 
Published: August 2014

Abstract
Tumor progression is influenced by the dynamic interplay between the genetically-modified epithelium and the associated microenvironment. We previously showed that the extra-cellular matrix (ECM) progressively stiffens as mammary tumors evolve, and that stiffening the ECM promotes malignant transformation while inhibiting ECM stiffening reduces tumor progression (Levental et al., 2009; reviewed in Butcher et al., 2009). Yet breast cancers also exhibit elevated influx of inflammatory cells and tissue inflammation promotes tumor progression by fostering angiogenesis and enhancing tumor cell growth and motility (Ruffell et al., 2011). Tumor-associated macrophages additionally stimulate stromal fibroblasts, implying that tissue inflammation could promote malignancy by stiffening the ECM. To address this possibility, we explored the relationship between ECM tension and macrophages in human breast cancer and during mammary tumor development in transgenic mice. Using fresh and archived tissue samples, we quantified a progressive increase in ECM remodeling and stiffening as human breast tumors and mouse mammary cancers developed. We found that the ECM associated with triple negative breast cancers was almost twice as stiff as the ECM adjacent to ER+/PR+ tumors and that ECM stiffness correlated significantly with increased numbers of infiltrating activated macrophages. Consistently, we established a positive correlation between tumor progression, elevated mechanosignaling, ECM stiffness and tissue inflammation in both human and mouse tissue. However surprisingly, when macrophages were depleted from the mammary glands of MMTV-PyMT tumors, ECM tension did not change. Instead we found that inhibiting lysyl oxidase activity to decrease collagen cross-linking and ECM stiffness reduced the activation state of the macrophages within the mammary glands of 14-week old mice. Consistently, in vitro studies showed that ECM tension potentiates the expression of pro-inflammatory chemokines and increases levels of phosphoStat3 and that ECM tension directly modifies macrophage polarity. These findings suggest that ECM tension may promote malignancy either by directly regulating macrophage activity or indirectly through enhancing expression of pro-inflammatory chemokines. Further studies are now underway to explore these findings and to clarify their impact on tumor progression and response to therapy.
Acknowledgements: supported by W81XWH-05-1-0330 and R01 CA138818-01A1 to VMW, 1U01 ES019458-01 to VMW and ZW, and P50 CA 58207 to JG, VW, SH and LC, U54CA143836-01 to JL and VW, and Susan G. Komen for the Cure PSF12230246 to IA.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S2-06.
Abstract S5-05: Postneoadjuvant treatment with zoledronate in patients with tumor residuals after anthracyclines-taxane-based chemotherapy for primary breast cancer – The phase III NATAN study (GBG 36/ABCSG XX)
Authors: von Minckwitz G , Rezai M , Eidtmann H , Tesch H , Huober J , Gerber B , Zahn DM , Costa S , Gnant M , Blohmer JU , Denkert C , Hanusch C , Jackisch C , Kümmel S , Fasching PA , Schneeweiss A , Paepke S , Untch M , Nekljudova V , Mehta K , Loibl S 
Published: August 2014

Abstract
Background: Patients with residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemoresistant breast cancer. Adjuvant treatment with bisphosphonates is considered to reduce the relapse risk predominantly in estrogen-deprivated patients.
Methods: Patients who had invasive tumor residuals (ypT1-4 or ypN+) after a minimum of 4 cycles of anthracycline-taxane-containing NACT were eligible to the NATAN study. Patients were randomized within 3 years after surgery to receive zoledronate 4 mg i.v. (plus 1000 mg Ca2+ and 880 I.U. vitamin D daily) for 5 years vs. observation. Zoledronate was given q 4 weeks for the first 6 months, q 3 months the following 2 years, and q 6 months for the last 2.5 years. Patients with hormone receptor (HR)-positive disease received letrozole for 5 years if postmenopausal, or tamoxifen, if premenopausal. Adjuvant trastuzumab for HER2-positive disease was allowed since an amendment in 2007. Stratification factors were HR, time since surgery, age, and center. Primary objective was event-free survival (EFS). 654 patients and 316 events were required to observe an increase of 5yr EFS from 58% to 67.2% (hazard ratio 0.73). Secondary objectives were to determine overall survival, EFS with respect to the interval between surgery and randomization, bone-metastasis-free-survival, toxicity of and compliance to zoledronate, the predictive value of breast tumor response to NACT on the effect of postoperative treatment and the prognostic impact of chemotherapy induced amenorrhea in premenopausal patients. An interim analysis for high efficacy at 158 observed events was planned in the protocol; in agreement with study IDMC a Bayesian analysis for futility with futility boundary of 15% will be performed at the same time.
Results: Between 2/2005 and 5/2009 693 patients were enrolled. Time between surgery and randomization was &lt;4 months in 48.4%, 4-12 months in 34.5%, and 13-36 months in 17.1% of patients. The median age was 50.9 yrs (range 33.7-88.2), 72.3% of patients were postmenopausal. 82% had HR-positive and 19% HER2-positive disease. During a median follow up of 48 months 154 events were observed so far.
Conclusion: This is the first post-neoadjuvant phase III study. Analysis of the primary endpoint will be presented in case the IDMC will release of the results of the futility analysis.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-05.