bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P2-11-17: L-dex ratio in detecting and diagnosing breast cancer-related lymphedema: Reliability, sensitivity, and specificity
Authors: Fu MR , Cleland CM , Guth AA , Kayal M , Haber J , Cartwright F , Kleinman R , Kang Y , Scagliola J , Axelrod D 
Published: August 2014

Abstract
Background: It remains a great challenge to accurately diagnose breast cancer-related lymphedema. Advances in bioelectrical impedance analysis (BIA) permit the assessment of lymphedema by directly measuring lymph fluid changes. Despite its value in assessing lymphedema, the use of BIA in clinical settings is still very limited. In part, this may be due to anecdotal complaints from clinicians about BIA's ability to identify true case of lymphedema in the clinical settings using L-Dex ratio &gt;+10 as the cutoff point for lymphedema diagnosis. This may also be due to lack of large clinical data to support the reliability, sensitivity, and specificity of using L-Dex ratio. The objective of the study was to examine the reliability, sensitivity, and specificity of BIA in a clinical setting.
Methods: BIA was used to measure lymph fluid changes. Data were collected from 250 women, including healthy female adults, breast cancer survivors with lymphedema, and those at risk for lymphedema. Reliability, sensitivity, specificity and area under the ROC curve were estimated.
Results: BIA ratio, as indicated by L-Dex ratio, was highly reliable among healthy women (ICC = 0.99; 95% CI = 0.99 - 0.99), survivors at-risk for lymphedema (ICC = 0.99; 95% CI = 0.99 - 0.99), and all women (ICC = 0.85; 95% CI = 0.81 - 0.87); reliability was acceptable for survivors with lymphedema (ICC = 0.69; 95% CI = 0.54 to 0.80). The L-Dex ratio with a diagnostic cutoff of &gt;+7.1 discriminated between at-risk breast cancer survivors and those with lymphedema with 80% sensitivity and 90% specificity (AUC = 0.86).
Conclusion: The L-Dex ratio may have a role in clinical practice despite its cost to add confidence in the diagnosis of arm lymphedema among breast cancer survivors. Lymphedema is a progressive and debilitating condition and early treatment usually leads to better clinical outcomes, given that BIA using a diagnostic cutoff of L-Dex ratio &gt; +7.1 still misses 20% of true lymphedema cases, it is important for clinicians to integrate other assessment methods (such as self-report, clinical observation, or perometry) to ensure the accurate diagnosis of lymphedema.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-17.
Abstract P2-14-01: Breast cancer patients with HER2 low-expression: An under-recognized group at significant risk for recurrence
Authors: Vreeland TJ , John BS , Trappey AF , Schneble EJ , Hale DF , Clifton GT , Shumway NM , Perez SA , Papamichail M , Ponniah S , Peoples GE , Mittendorf EA 
Published: August 2014

Abstract
Background:
HER2 over-expression is associated with more aggressive malignant disease. The introduction of trastuzumab and other HER2-directed therapies, however, has led to improved prognosis for patients (pts) with HER2 over-expressing (OE) tumors. Currently, no HER2-targeted therapies are available for patients with HER2 low-expressing (LE) (1+, 2+ by IHC) tumors. We are conducting a randomized, controlled Phase II trial of multiple peptide vaccines enrolling patients with any level of HER2 expression (1+, 2+ and 3+). Here, we report survival data based on levels of HER2 expression in our unvaccinated, control pts.
Methods:
After standard of care therapy, disease-free, high-risk BCa pts were randomized to receive either peptide+GM-CSF (Vaccine Group, VG) or GM-CSF alone (Control Group, CG) in six, monthly doses followed by four boosters every six months. Pts were prospectively followed for recurrence. Demographic information was available for all pts and was compared between groups using chi square or fisher exact tests. Disease-Free Survival (DFS) was compared using log rank.
Results:
To date, we have enrolled 196 pts in the CG. 96 pts had HER2 OE tumors, 100 had LE tumors. The only significant demographic difference between the CG OE and LE groups was more ER/PR positive patients in LE (LE 72% vs OE 51%, p = 0.008). 83% of CG OE pts received trastuzumab, 3% of CG LE pts received trastuzumab. At a median f/u of 30 mo, DFS was significantly higher for CG OE vs CG LE (92.5% v 65.5%, p = 0.001).
Conclusions:
In the cohort of control pts from our ongoing vaccine trial, conducted in an era when Tz has been standard of care therapy for patients with HER2 OE tumors, we have shown that HER2 LE pts are at higher risk of recurrence than OE pts, despite having more ER/PR positive. This calls for increased efforts to develop novel therapies for patients with HER2 LE disease. We have previously shown a trend towards increased DFS with the HER2 vaccines, AE37 (p = 0.13, median f/u 22 mo) and E75 (p = 0.16, median f/u 60mo) in HER2 LE pts, suggesting that these vaccines may represent one such novel therapeutic approach.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-14-01.
Abstract P2-16-01: A randomized, phase II, multicenter, double-blind, placebo-controlled trial evaluating onartuzumab with or without bevacizumab in combination with weekly paclitaxel in locally recurrent or metastatic triple-negative breast cancer (TNBC)
Authors: Dieras V , Yardley D , Romieu G , Valero V , Isakoff S , Koeppen H , Thurm H , Teng M , Campone M , Mocci S 
Published: August 2014

Abstract
Background: Dysregulation of the hepatocyte growth factor (HGF)/MET pathway has been observed in many malignancies. In patients with TNBC, overexpression of MET has been shown to be associated with poor prognosis. Onartuzumab (MetMAb) is a recombinant, humanized, monovalent, monoclonal antibody directed against MET, which selectively blocks ligand binding and subsequent HGF activation. A recent phase 2 trial demonstrated improved progression-free survival (PFS) and overall survival (OS) when onartuzumab was added to erlotinib for patients with MET 2+/3+ non-small-cell lung cancer (NSCLC).
Methods: Patients with locally recurrent or metastatic TNBC who had received 0 or 1 prior therapies for metastatic disease were enrolled, provided tumor sample, and randomized (1:1:1) to receive paclitaxel (P) + bevacizumab (B) + onartuzumab (O); P+O; or P+B. Dosing regimens were given IV q4w: P 90 mg/m2 d1, 8 & 15; B 10 mg/kg d1 & 15; O 10 mg/kg d1 & 15. Treatment continued until disease progression or unacceptable toxicity or death; crossover was not permitted. Stratification was by number of metastatic sites (&lt;3, ≥3), number of prior MBC regimens (1 vs 2), and disease-free interval for first-line patients (≤6 months, &gt;6 months). The primary endpoint was PFS; secondary endpoints included OS, objective response rate (ORR), and safety. MET immunohistochemistry (IHC) was performed centrally for exploratory analyses.
Results: 185 patients were enrolled from 30 US and 37 EU sites: median age was 53 years (range 30-79); 77% and 23% were treated in the first- and second-line settings, respectively. Baseline characteristics were balanced. Efficacy data for the ITT population are shown in Table 1. The distribution of MET expression using the NSCLC diagnostic algorithm is shown in Table 2. The MET 2+/3+ group was too small for efficacy analyses. Frequently observed AEs (all grades) included peripheral edema (58% vs 59% vs 18%), fatigue (47% vs 41% vs 48%) and diarrhea (53% vs 22% vs 50%), in the P+B+O vs P+O vs P+B arms, respectively. No new safety signals were observed.
Table 1Table 1ITT populationP+B+O n = 63P+O n = 60P+B (control) n = 62Median PFS, months7.35.47.2HR vs control (95% CI)1.08 (0.69 - 1.70)1.74 (1.13 - 2.78)-Median OS, months14.713.417.4HR vs control (95% CI)1.35 (0.74 - 2.44)1.88 (1.00 - 3.54)-ORR,% (95% CI)42 (29 - 57)28 (16 - 41)55 (41 - 68)
Conclusions: In the ITT population, the addition of O to either P+B or to P alone did not improve PFS and other clinical outcomes compared with P+B alone. Further exploratory subgroup analyses are ongoing.
Table 2Table 2MET IHC score01+2+3+Not availablen (%)81 (44)75 (41)21 (11)1 (0.5)7 (4)
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-01.
Abstract P2-17-01: The PI3K inhibitor GDC-0032 is selectively potent against PIK3CA mutant breast cancer cell lines and tumors
Authors: Wallin JJ , Edgar KA , Guan J , Sampath D , Nannini M , Belvin M , Friedman LS 
Published: August 2014

Abstract
Mutations in the phosphoinositide-3 kinase alpha isoform (PIK3CA) are frequent in breast cancer and activate the PI3K signaling pathway. We discovered GDC-0032, a selective, potent, orally bioavailable inhibitor of PI3Ka with a Ki = 0.2nM, and with reduced inhibitory activity against PI3Kβ. This selectivity profile, and excellent pharmacokinetic and pharmaceutical properties, allowed for greater efficacy in vivo at the maximum tolerated dose relative to a pan Class I PI3K inhibitor in PIK3CA mutant xenografts. Notably, GDC-0032 preferentially inhibited PIK3CA mutant cells relative to cells with wild-type PI3K. GDC-0032 potently inhibits signal transduction downstream of PI3K and induces apoptosis at low concentrations in breast cancer cell lines and xenograft models that harbor PIK3CA mutations. The mutant-bias of GDC-0032 is linked to unique properties of GDC-0032, including cellular potency against the mutant isoform and reduction of receptor tyrosine kinase (RTK) signaling.
Endocrine therapies such as letrozole are commonly used treatment options for metastatic Hormone Receptor positive (HR+) breast cancer but many patients ultimately relapse. Due to the importance of PI3K in breast cancer, PI3K inhibitors such as GDC-0032 are attractive for combination with endocrine therapies. GDC-0032 was evaluated in breast cancer lines and models in combination with letrozole, and assayed for cellular viability, modulation of PI3K pathway, modulation of ER pathway markers, and apoptosis induction. The combination of GDC-0032 and letrozole decreased cellular viability and increased apoptosis relative to either single agent. We observed cross-talk between the PI3K and ER pathways that suggest a mechanism of action for the combination. In a secreted factor screen we found that multiple soluble factors render breast cancer cells non-responsive to letrozole. It was discovered that many of these factors signal through the PI3K pathway and GDC-0032 in combination with letrozole was able to overcome the growth inhibition caused by the soluble factor. We also established letrozole resistant cell lines that grow independently of any estrogen source. These letrozole resistant lines have elevated PI3K pathway signaling and are still sensitive to GDC-0032. Taken together, these data provide rationale for evaluating GDC-0032 in combination with endocrine therapies for ER+ breast cancer treatment in the clinic.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-17-01.
Abstract P3-13-06: A prospective phase II trial of vinorelbine plus oxaliplatin in second- or third-line metastatic triple-negative breast cancer
Authors: Wang Z , Zhang J , Wang L , Hu X , Wang B , Cao J , Lv F , Zhen C , Zhang S , Shao Z 
Published: August 2014

Abstract
Purpose: Patients with metastatic triple-negative breast cancer (mTNBC) typically have a poor prognosis and limited treatment options. Previous study showed biweekly combination of vinorelbine and oxaliplatin (NVBOX) at doses of 30 mg/m2 and 90 mg/m2, respectively, is highly active and well tolerated as first-line treatment for patients with metastatic breast cancer. The purpose of this study (NCT 01528826) was to prospectively evaluate the efficacy and toxicity of NVBOX in second- or third-line mTNBC.
Methods: Eligible patients were female with 18–70 years old and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, and had mTNBC that had progressed after 1or 2 prior chemotherapy regimens in the metastatic setting. A period of 4 weeks (NVBOX twice) was considered as one treatment cycle and the maximum cycles were 6. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety.
Results: Between Dec 2011 and Nov 2012, forty-four patients were recruited [median age 47; 77.3% with viceral metastasis, 100% had been exposed to anthracyclines and/or taxanes; 56.8% cis/carbo-platin pretreated for MBC; 38.6% with time to progression (TTP) of 1-2 previous regimens before recruitment ≤ 3 months]. The overall response rate was 31.6% (1 complete response, 11 partial responses) and 10 achieved stable diseases (7 lasting more than 6 months) in 38 evaluable patients. After a median follow-up of 12.8 months, the median PFS and OS were 4.3 (95% CI, 3.6–5.0) months and 12.6 (95% CI, 8.1–17.0) months, respectively. PFS was significantly shorter in patients with disease free interval (DFI) ≤ 1year (HR = 2.10; 95% CI, 1.05–4.21; P = 0.037) and TTP of 1-2 previous regimens before recruitment ≤ 3 months (HR = 3.39; 95% CI, 1.66–6.89; P &lt; 0.001). Also, these two factors were two independent predictors for the poor OS (HR = 5.45; 95% CI, 2.08–14.32; P &lt; 0.001 and HR = 4.09; 95% CI, 1.73–9.68; P &lt; 0.001). For 34 second line patients, prior platinum in the first line was a factor significantly compromise the PFS (HR = 2.29; 95% CI, 1.03–5.10; P = 0.043). Dose adjustment happened in 14 patients (31.8%) due to adverse events (AEs). Grade 3/4 hematologic toxicities were neutropenia (70.5%), thrombocytopenia (27.3%) and anemia (15.9%). Four patients experienced febrile neutropenia. The most frequent grade 3/4 non-hematologic toxicities were constipation (20.5%) and vomiting (11.4%). Two patients developed grade 3 NVBOX-related peripheral neurotoxicity. There were no treatment-related deaths.
Conclusion: We conclude that biweekly NVBOX regimen is effective with a good safety profile in the second- or third-line mTNBC, which warrants further investigation in a phase III study.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-06.
Abstract P4-01-18: A discrete population of p63+/K5/14+ cells implicated in the pathogenesis of salivary gland-like tumors of the breast
Authors: Boecker W , Stenman G , Loening T , Andersson MK , Berg T , Buchwalow I 
Published: August 2014

Abstract
Background: Salivary gland-like tumors are currently subdivided into those with and those without myoepithelial differentiation. Furthermore, they show a wide range of differentiation patterns including squamous differentiation. Many authors believe that the myoepithelial cell plays a major role in this context. However, currently little is known about the evolution and cellular differentiation of these tumors.
Material and Methods: For that reason, we performed an in situ Triple Immunofluorescence Lineage/Differentiation Tracing (isTILT) and qRT-PCR study of basal (K5/K14), glandular (K7/K8/18), and epidermal-specific squamous (K10) keratins, p63, and smooth muscle actin (SMA; myoepithelial marker) with the aim to trace different cell lineages and define their cellular hierarchy in tumors. We investigated 50 cases of salivary gland-like tumors of the breast (11 Adenoid-cystic carcinomas, 9 (adeno-)myoepithelial tumors, 8 adeno-squamous carcinomas including 12 syringomas of the nipple, 10 squamous cell carcinomas), and their corresponding counterparts. In 4 cases, the corresponding cell cultures were also analysed.
Results: All tumor types contained p63+/K5/14+ progenitor cells in varying frequencies from a few percent up to 15%. These tumor cells were found to differentiate to glandular (K8/18-positive) or to myoepithelial (SMA-positive) lineage specific cells; they were also shown to generate various heterologeous cell differentiations such as squamous and mesenchymal progenies. p63 was partly retained in the myoepithelial and squamous cells lineages but not in the glandular cells lineage. These data were corroborated by RNA-expression results. The corresponding counterpart tumors of the salivary/lacrimal glands were found to have identical cellular compositions.
Conclusions: Our findings clearly demonstrate that p63+/K5/14+ tumor cells in salivary gland-like tumors of the breast and in their counterparts are key players in tumor development and differentiation. They undergo a transition from their original p63+/K5/14+ precursor state to new p63+/K5/14+/SMA+ myoepithelial and/or p63+/K10+ squamous lineages, and/or to a K7+/K8/18+ glandular state, which can be pictured by isTILT-experiments and RNA-expression studies. Given the phenotypic similarity of p63+/K5/14+ tumor cells to physiological counterparts in the normal breast and salivary duct epithelium and considering the fact that these cells may give rise to a number of different progenies with specific differentiation lineages, we suggest that this cell and its physiological differentiation potential provides an important ontogenetic key to a better understanding of these tumors.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-18.
Abstract P5-08-05: The influence of doxorubicin on PTEN and PI3K-Akt-mTOR signaling in human breast cancer
Authors: Austreid E , Knappskog S , Lønning PE , Eikesdal HP 
Published: August 2014

Abstract
Background:
De novo as well as acquired resistance are common features of anthracycline therapy in breast cancer. The PTEN tumor suppressor gene is frequently inactivated in human breast cancer, leading to induction of PI3K-Akt-mTOR signaling, which facilitates cell growth, survival, invasion and ultimately tumor progression. Upregulation of the PI3K-Akt-mTOR pathway has been suggested as a possible mechanism of anthracycline resistance, but there is limited data in the clinical setting, including its influence on PTEN expression.
Methods:
The early PTEN response to doxorubicin was assessed in vitro in MCF7 (estrogen receptor positive) and MDA-MB231 (triple negative) human breast cancer cell lines 24 hours after the initiation of chemotherapy. Tumor samples from thirty patients with locally advanced breast cancer were analyzed for PTEN expression levels and PI3K-Akt-mTOR signaling before and after neoadjuvant anthracycline therapy. The early effect of anthracyclines on PTEN expression is currently being evaluated in human breast cancer samples 24 hours after the initiation of chemotherapy. Mice bearing MCF7 and MDA-MB231 xenografts will be used to assess the potential of PI3K-Akt-mTOR signal transduction inhibitors in preventing anthracycline resistance.
Results:
PTEN expression was found to be profoundly downregulated in both MCF7 and MDA-MB231 cell lines, 24 hours after exposure to doxorubicin at their respective IC50. An increase in Akt1 protein levels in both cell lines was observed in the same setting. In 19 out of 30 human breast cancers PTEN levels increased after a median of 16 weeks neoadjuvant doxorubicin treatment. No difference between estrogen receptor positive and negative breast cancers was observed. The increase in PTEN was accompanied by an increase in fibrotic tissue in the tumor interior. There was no correlation between PTEN level or treatment-induced alterations in PTEN expression and response rates or recurrence-free survival (RFS). The results from our currently ongoing experiments will be presented.
Conclusion:
PTEN expression increases in the majority of human breast cancers during long-term exposure to doxorubicin. However, PTEN is greatly downregulated, with corresponding Akt1 increase, 24 hours after exposure to high doses of doxorubicin in vitro. These results indicate different effects of short- and long-term exposure to doxorubicin, which may be of importance to the development of anthracycline resistance, and to understand at what time a combinational approach with inhibitors of the PI3K-Akt-mTOR pathway will be beneficial. Current efforts are aimed at evaluating the potential of such inhibitors to counteract doxorubicin resistance in this setting.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-08-05.
Abstract S4-02: Integrated genomic analyses of members of protein kinase C family identifies subtype specific alterations as novel therapeutic targets
Authors: Natrajan RC , Leonidou A , Brough R , Frankum J , Wai PT , Ng CK , Reis-Filho JS , Lord CJ , Ashworth A 
Published: August 2014

Abstract
Introduction
Members of the protein kinase C family are serine/threonine kinases that are involved in proliferation, apoptosis, cell survival and migration, and have been implicated in tumorigenesis. Recently PRKCE has been found to be up-regulated in triple-negative (TN) breast cancers and has been proposed as a target for therapeutic intervention. The aims of this study were to determine i) whether different members of the PKC family are dysregulated and/ or mutated in specific subtypes of breast cancer, ii) to investigate the impact of silencing or overexpression of members of the PKC family in cell line models representative of the different breast cancer subtypes.
Material and methods:
We obtained expression and mutational data from the cancer genome atlas (TCGA) project from 567 and 640 samples subjected to microarray-based gene expression profiling and whole exome sequencing, respectively. Pair-wise SAM analysis of TCGA gene expression data was performed to identify differential expression between subgroups (ER+, HER2+ and TN). Potential driver mutations were identified through the algorithm CHASM. Subtype specific dependencies were identified from the re-analysis of publicly available siRNA kinome-wide screens in a panel of 20 breast cancer cell lines. In vitro assessment of gene overexpression was assessed in MCF10A cells by wound healing scratch assays and 3D growth in Matrigel.
Results
PRKCA, B, I and Q were expressed at significantly higher levels in TN breast cancers. Higher expression of PRKCE was significantly associated with ER-negativity, whereas high PRKCD expression was associated with ER-positivity. Analysis of siRNA kinome-wide screen data resulted in a significant reduction in survival associated with PRKCI and PRKCE in ER-negative cells, PRKCQ in triple-negative cells, and PRKCD in ER-positive cells. Furthermore meta-analysis of published exome and whole genome sequencing data identified potentially activating recurrent kinase domain mutations in PRKCB (0.93%), Q (1.25%) and Z (0.93%), with mutations in PRKCZ being associated with higher gene expression. Forced expression of wild-type PRKCQ and PRKCZ in MCF10A cells resulted in the formation of irregular acini in 3D cell culture and expression of wild-type PRKCZ resulted in increased migration.
Conclusions
Differential expression of members of the protein kinase C family, are associated with different molecular subtypes of breast cancer. Furthermore, we have shown that breast cancer cells are dependent upon expression of these family members in vitro, which are associated with different cellular phenotypes.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S4-02.