bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oncoplasty for lateral breast cancers.
Authors: Salmon RJ , Reyal F , Berry M , Ballester M , Couturaud B , Fitoussi A 
Published: December 2010

Abstract
Abstract #5158
Introduction: 65% of breast cancers develop in the lateral pole, particularly superiorly. Following conservative treatment, , tumourectomy may produce a typical deformity of superolateral nipple-areolar complex (NAC) deviation. This unaesthetic deformity, is exaggerated by the post-operative irradiation mandated by contemporary breast conserving therapy. Primary utilisation of the oncoplastic technique, 'lateral mammaplasty', allows both the avoidance of such deformities and wider excision margins.&#x2028; Patients and methods: The principle behind the technique is the combination of a wide, wedge-shaped tumourectomy combined with NAC repositioning on a de-epithelialised dermoglandular pedicle. Sentinel lymph node biopsy or formal axillary dissection may be performed simultaneously either via a separate or combined incision for inferior and superior lateral mammaplasties respectively. Aesthetic outcomes were assessed on a five-point scale with 1 being excellent and 5 poor.&#x2028; Results: eighty-six patients, with a mean age of 53 years (range 29 – 75) underwent lateral mammaplasty. Fifty-five (64%) were palpable and 73 (86%) had simultaneous axillary surgery. Mean tumour size pre- and post-operatively were 29.8 mm (8 – 81) and 33.6 mm (0 – 140) respectively. Mean excision weight was 150g (24 – 484). Eleven (12.8%) required revisional surgery due to involved or close margins and the aesthetic outcome was graded highly satisfying or satisfying in 68 (79%).&#x2028; Discussion: lateral mammaplasty has been found to be simple to perform with a short learning-curve. With clear excision margins in 87.8%, it is oncologically sound and compares favourably with simple tumourectomy. It should be considered when the tumour-to-breast volume ratio anticipates an aesthetic deformity. We have found it to be particularly satisfactory after neo-adjuvant chemotherapy for large volume tumours when a positive clinical response allows conservative surgery. It is also useful for revisional surgery in cases of involved or close margins following initial tumourectomy.&#x2028; Conclusion: lateral mammaplasty became routine in our institution as it allows, with the assistance of a simple oncoplastic procedure, highly satisfying aesthetic outcomes and the added security of wide excision margins.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5158.
Metastasis-associated microtentacles are induced in detached and circulating breast tumor cells by expression of the microtubule-binding protein, Tau.
Authors: Matrone M , Whipple R , Balzer E , Cho E , Yoon J , Martin S 
Published: December 2010

Abstract
Abstract #55
Detached human breast tumor cell lines produce microtentacles composed of a unique kinesin-dependent coordination of vimentin filaments and detyrosinated microtubules. Compelling in vivo studies show that a mechanism consistent with microtentacles is responsible for the attachment of circulating tumor cells to blood vessel walls. However, the molecular regulators of microtentacle extension have only begun to be defined. Increased expression of the microtubule-binding protein, Tau, is associated with poor patient outcome in breast cancer, but the mechanism by which Tau protein affects prognosis remains unclear. We report here that expression of Tau directly regulates the formation of metastasis-associated microtentacles in detached and circulating breast tumor cells. First, increased expression of Tau correlates with increased microtentacle frequency in a panel of human breast tumor cell lines. Endogenous Tau protein colocalizes with tubulin microtentacles in cells detached from extracellular matrix. Exogenous expression of Tau significantly increases microtentacle frequency in weakly invasive breast tumor cell lines. Tau-induced microtentacles are longer, thicker and more rigid than those in cell lines without Tau expression. Although there is increasing interest in targeting the actin cytoskeleton to reduce tumor cell motility and division, our results indicate that breast tumor cells with high Tau expression have particularly dramatic increases in microtentacles when treated with inhibitors of actin polymerization. Likewise, tubulin-stabilizing compounds, like paclitaxel, increase microtentacles and may be ill-advised in patients with high Tau expression. Indeed, clinical studies show that high Tau expression increases the likelihood of recurrence following paclitaxel treatment. We observed an enrichment of Tau in metastatic tumors compared to matched primary tumors. So while stabilizing microtubules and disrupting actin filaments can each decrease tumor cell growth, it is important to consider the effects of these treatments on Tau-expressing cells to avoid accidentally enhancing the metastatic potential of circulating tumor cells while targeting cell division.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 55.
c-MYC amplification and correlation with patient outcome in early stage HER2+ breast cancer from the NCCTG adjuvant intergroup trial N9831.
Authors: Perez EA , Reinholz MM , Dueck AC , Wiktor AE , Lingle WL , Davidson NE , Martino S , Kaufman PA , Kutteh LA , Jenkins RB 
Published: December 2010

Abstract
Abstract #56
Background: Recent findings from NSABP B-31 suggested that breast cancer (BC) patients (pts) with c-MYC (MYC)/HER2 co-amplification in their primary tumors may benefit more in terms of disease-free survival (DFS) from adjuvant trastuzumab (n=471; p&lt;0.0001, HR 0.24; 13 vs. 51 events) than those pts with only HER2 amplification in their primary tumors (n=1078, p=0.007, HR 0.63; 55 vs. 82 events).&#x2028; Purpose: The overall objective of this analysis is to determine the association between MYC/HER2 co-amplification and outcome of pts randomized to receive chemotherapy alone (Arm A) or chemotherapy with concurrent trastuzumab (Arm C) on N9831.&#x2028; Patients/Methods: This analysis included 868 pts from the HER2+ NCCTG N9831 Intergroup adjuvant trastuzumab phase III clinical trial on Arms A or C. Fluorescent in situ hybridization (FISH) was performed at a central laboratory, Mayo Clinic Clinical Cytogenetics Laboratory, using dual probe mixtures for HER2 (17q11.2-12/centromere 17) and for MYC (8q24/centromere 8). The HER2 amplification status in whole tissue sections was evaluated to determine eligibility of pts for N9831. Tissue microarrays containing three cores from each patient's tumor were analyzed for MYC amplification status. The gene and centromere copy number as well as the distribution of the signals for each marker were determined in sixty non-overlapping interphase nuclei.&#x2028; Results: Of 273 pts with completed FISH analyses, 34 (12%) pts had MYC amplification. The rate of MYC amplification was similar across arms (18/135 [13%] vs. 16/138 [12%]; ChiS p=0.66). Co-amplification of MYC/HER2 was observed in 32 (12%) pts with similar co-amplification rates across arms (17/135 [13%] vs. 15/138 [11%]; ChiS p=0.66). Based on preliminary analyses, MYC amplification and MYC/HER2 co-amplification do not appear to be associated with race, menopausal status, hormone receptor status, nodal status, tumor histology, tumor grade, or tumor size (all ChiS p&gt;0.05); however, MYC amplified pts were significantly younger than MYC non-amplified pts (mean 46.4 vs. 51.0, t-test p=0.02) and MYC/HER2 co-amplified pts were significantly younger than MYC/HER2 non-co-amplified pts (mean 45.9 vs. 51.0, t-test p=0.01).&#x2028; Conclusions: In our initial analyses of 239 pts, we observed a lower frequency of MYC/HER2 co-amplification than the previously reported 30% for NSABP B-31. Complete FISH analyses of 868 pts in N9831 and association with DFS will be presented.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 56.
A 6 gene molecular predictor of lapatinib related benefit: from cell line models to clinical trials.
Authors: Gray J , Das D , Spellman P , Wang N , Kuo W , Wyrobek A , Bhattacharya S , Press M , Di Leo A , Ellis C , Arbushites M , Casey M , Gagnon R , Koehler M 
Published: December 2010

Abstract
Abstract #58
Background: Identification of molecular predictors of response is an important aspect of individualized cancer treatment. Responses to lapatinib (L), an oral inhibitor of HER2 and EGFR, approved in combination with capecitabine for HER2+ metastatic breast cancer (MBC), were evaluated in a panel of BC cell lines. Computational approaches were used to identify transcripts that quantitatively associate with response to L in the cell line panel that were then tested in 2 clinical trials.&#x2028; Methods: The clinical utility of a 6-gene predictor was tested retrospectively using a branched-chain DNA assay in paraffin-embedded archival tumor tissue from patients (pts) with HER2 negative or untested MBC tumors enrolled in a phase III trial of paclitaxel (P) vs. P+L, and from pts with HER2 positive MBC enrolled in a L monotherapy trial. Expression of HER2 transcript using the branched-chain assay was compared with HER2 fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) status; discordant cases were analyzed. Response patterns for pts with HER2+ tumors and a computational model that predicts L sensitivity or resistance is described.&#x2028; Results: Ingenuity analysis of the mRNA predictors of response to L identified in the BC cell line panel revealed saturated gene networks with HER2 as a major node. The 6-gene predictor of response was comprised of 2 genes associated with sensitivity to L: HER2 and GRB7; 4 genes associated with resistance to L: CRK, ACOT9, FLJ31079, and DDX5. Expression results for the 6 genes and progression-free survival (PFS) data were available for 159 pts on L+P. Median PFS in the branched-chain HER2+ group was 32.9 wks vs. 22.4 wks in the HER2-negative group. The 6-gene predictor was used to predict response to L in the HER2+ pts. Comparison of PFS in the 24 “L sensitive” tumors vs. 25 “L resistant” tumors indicated that the predictor, derived from cell-line analyses, had the potential to predict clinical response to L in pts treated with L+P (HR=0.58; 95% CI=0.30-1.11; p=0.07). The 6-gene predictor was further tested in an independent L monotherapy study in pts with HER2 FISH+ MBC. Comparison of PFS in the 24 “L sensitive” tumors vs. 28 “ L resistant” tumors reconfirmed the potential of the 6-gene predictor to enrich for HER2+ pts most likely to experience clinical benefit from L (HR=0.40; 95% CI=0.19-0.84; p=0.015). Further testing is ongoing.&#x2028; Conclusions: This study suggests that molecular predictors of clinical response can be developed through an analysis of response from a collection of 50 BC cell lines. The identification of a L specific 6-gene assay is promising as a clinical predictor of benefit from L in pts with HER2+ BC.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 58.
Comparative breast tumor imaging to identify the expression of type I IGF receptor (IGF1R) by anti-IGF1R antibody-conjugated small molecule fluorophore or quantum dots in vivo.
Authors: Zhang H , Zeng X , Yee D 
Published: December 2010

Abstract
Abstract #6001
The type I insulin-like growth factor (IGF) receptor (IGF1R) is a transmembrane receptor tyrosine kinase involved in breast cancer proliferation, survival, and metastasis. Several antibodies against IGF1R, including some in clinical trials, downregulate the level of IGF1R both in cell line studies and in in vivo animal experiments. Thus, this downregulation is a biodynamic marker of antibody delivery to the tumor. To date, identification of IGF1R expression and its downregulation in vivo in a non-invasive way is still challenging. In this study, we sort to use two different fluorescent technologies, small molecule fluorophores, or quantum dots (QDs), to detect receptor expression and its downregulation by antibodies in vivo. Alexa 680 is a small molecule fluorophore that can be excited with a peak emission at 705 nm. QDs are nanocrystals that emit fluorescence upon excitation, and QDs with a peak emission at 705 nm was used in this study. Both Alexa 680 and QDs were conjugated with AVE-1642, a humanized anti-IGF1R antibody developed by sanofi-aventis. After conjugation, they both were able to detect the expression of IGF1R and its downregulation in in vitro cell line studies. We used mouse xenograft tumor models to examine their efficacies in vivo. AVE-1642 conjugated Alexa 680 or QDs (705 nm) was intravenously delivered to mice bearing mammary xenograft tumors that express IGF1R. After 24 hours of circulation, Alexa 680 fluorescence was shown to solely localize to the xenograft tumor, with little non-specific targeting to other tissue or organs in mice. In addition, Alexa 680 fluorescence was diminished in tumors that had downregulated IGF1R by antibody pretreatment. In contrast, conjugated QDs fluorescence was mainly localized to liver, spleen, bone marrow and lymph nodes, with very small amount of QDs in the xenograft tumors. The QDs fluorescence in xenograft tumors remained unchanged even when IGF1R was downregulated by antibody pretreatment. Furthermore, we identified that QDs were mainly localized to the hepatic sinusoids, and subsequently engulfed by Kupffer cells. Taken together, our data suggest that small molecule fluorophores, such as Alexa 680, are useful agents to detect the expression and downregulation of IGF1R in vivo. Our data provide valuable insight not only into the clinical development of anti-IGF1R antibodies, but also to other targeted therapy as well.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6001.
Metabolism-perfusion mismatch as assessed by PET varies with breast cancer phenotype and predicts response to neoadjuvant chemotherapy.
Authors: Specht JM , Kurland BF , Dunnwald LK , Doot RK , Gralow JR , Ellis GK , Linden HM , Livingston RB , Schubert EK , Mankoff DA 
Published: December 2010

Abstract
Abstract #6005
Background: Kinetic analysis of FDG and water PET can identify patterns of breast cancer metabolism and perfusion in patients receiving neoadjuvant chemotherapy (NC). Previously, we found that high pre-therapy glucose tumor metabolism relative to perfusion was associated with poor tumor pathologic response, early relapse, and death in patients with locally advanced breast cancer (LABC) treated with NC. This analysis examines tumor metabolism and perfusion as a function of tumor phenotype. Material and Methods: Tumor phenotype, defined by immunohistochemistry (IHC), was determined in 51 patients undergoing NC between 1995 and 2005. Luminal tumors were defined as those expressing either estrogen receptor (ER) or progesterone receptor (PR). The triple-negative (TN) phenotype was defined as ER and PR negative without HER2 overexpression by IHC or amplification by FISH. HER2 phenotype showed HER2 overexpression or amplification but were ER/PR negative. Women with LABC underwent dynamic [18F]-FDG and [15O]-water PET scans prior to NC. The FDG metabolic rate (MRFDG) and transport (FDG K1) parameters were calculated; blood flow (BF) was estimated from the water PET scan. Response to NC was determined from surgical specimens with pathologic complete response (pCR) defined as eradication of invasive tumor in the breast vs. other. Results: Of the tumors studied, 16 (31%) were TN, 30 (59%) were luminal, and 5 (10%) were HER2. pCR was observed in 4/16 (25%) TN tumors (95% CI: 0.10-0.50) compared to only 4/30 (13%) of luminal tumors (95% CI: 0.05-0.30) and 3/5 HER2 tumors. Linear regression of the association between PET parameters and phenotype (TN vs. luminal) found that TN was associated with higher MRFDG (p=0.007) and MRFDG/BF ratio (p=0.02), but not with BF (p=0.27). Only patients with low pre-therapy MRFDG/BF ratio (&lt;35 umol/mL) achieved a pCR. Using this value as an ad-hoc cutoff, 4/7 (57%) of TN patients with low ratios had a pCR, while 0/9 with higher ratios had pCR. In contrast, only 4/21 (19%) of the luminal patients with low ratios had a pCR (one-sided mid-p=0.04 for TN vs. luminal pCR rate for patients with MRFDG/BF &lt; 35 umol/mL). Discussion: These results demonstrate heterogeneity in breast tumor metabolism and perfusion as assessed by PET, and suggest a clinically relevant association between PET parameters and tumor phenotypes. The high MRFDG/BF ratio that predicts poor response to NC is more common in TN tumors; whereas in luminal or HER2 tumors, high MRFDG is generally matched with higher BF. Measurement of tumor metabolism and perfusion may identify a subset of tumors which are unlikely to respond to NC. Identification of such tumors may direct therapy toward those biologic targets most likely to overcome resistance.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6005.
DCE-MRI and dynamic FDG PET to monitor breast cancer response to neoadjuvant sunitinib in patients with locally-advanced breast cancer.
Authors: Specht JM , Partridge S , Dunnwald L , Doot R , Schubert E , Kurland B , Gralow J , Linden H , Gadi V , Ellis G , Mankoff D 
Published: December 2010

Abstract
Abstract #6006
Background: We are enrolling patients with locally-advanced (LABC) or inflammatory breast cancer on a phase II trial of neoadjuvant sunitinib and metronomic chemotherapy. The addition of sunitinib is hypothesized to increase rate of pathologic complete response (pCR) via its effect on tumor vasculature. Measurement of FDG PET and MRI parameters of metabolism and blood flow (BF) after a one week run-in of sunitinib alone provides an opportunity to evaluate in vivo pharmacodynamics of sunitinib which may be predictive of response and provide insight into mechanism of sunitinib activity. Materials and Methods: Patients with HER2 negative LABC participated in an imaging trial with pre-therapy [18F]-FDG PET and DCE-MRI (T0) followed by a one-week run-in of sunitinib 37.5 mg orally daily with a second PET and MRI on day 7 (T1). FDG metabolic rate (MRFDG), transport (FDG K1) and MR indices of tumor perfusion (peak enhancement (PE), signal enhancement ratio (SER), and washout volume(WV)) were assessed. Results: Metabolism and perfusion parameters are available for the first 3 patients treated on this trial. All patients presented with grade 3, HER2 negative LABC. DCI-MRI (left) and PET images (right) pre-therapy (T0, top) and after one week sunitinib (T1, bottom) are illustrated in Figure 1. DCE-MRI studies show gray-scale images with color-coded regional perfusion (SER) superimposed; red indicates high levels of perfusion and blue lower levels. Three different responses were observed and expressed as percent change T0 to T1: patient 1 had no significant change in metabolism (MRFDG) or perfusion (K1,SER, PE); patient 2 showed a decline in perfusion with decreases in K1 (-55%), SER (-19%), PE (-10%), and WV (-56%), but minimal change in MRFDG (+ 5.9%); while patient 3 had marked declines in perfusion K1 (-41%), SER (-25%), WV (-78%) and MRFDG (-59%). Discussion: These early data demonstrate the ability to measure changes in tumor metabolism and blood flow by PET and MRI and illustrate heterogeneity in tumor response to sunitinib. As patients complete neoadjuvant chemotherapy (NC), metabolism and perfusion parameters from mid-therapy (T2) and end-therapy (T3) imaging will be evaluated in the context of pCR versus other with the goal of exploiting functional imaging parameters to predict response to NC and elucidate mechanism of response to sunitinib and metronomic chemotherapy. Supported by grant from NCCN, SI11.&#x2028; &#x2028;
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6006.
Novel mouse model for studying role of ER-nongenomic actions in breast cancer.
Authors: Rajhans R , Cortez V , Nair SS , Tekmal RR , Kumar R , Vadlamudi RK 
Published: December 2010

Abstract
Abstract #601
Back ground: Estradiol (E2) and estrogen receptor (ER) signaling play a key role in development and progression of breast cancer. ER signaling is complex, involves coregulatory proteins and the status of ER coregulators in tumor cells plays an important role in hormonal responsiveness and tumor progression. In addition, ER also participates in non-genomic signaling events in the cytoplasm, however the significance of non-genomic signaling in mammary tumorigenesis remain unknown. PELP1/MNAR is novel ER coregulator that participates in ER genomic and non-genomic actions. PELP1 expression is deregulated in breast tumors and in a subset of tumors PELP1 is predominantly localized in the cytoplasm. Since PELP1 cytoplamsic localization promotes excessive activation of Src and AKT pathways, we hypothesized that PELP1 mediated excessive activation of ER-nongenomic functions may play a role tumorigenesis. To test this, we have generated MMTV-PELP1cyto TG model that uniquely express PELP1 in the cytoplasm of mammary glands that mimics the pathological situation of PELP1 localization seen breast cancer.&#x2028; Methods: As a means of targeting the expression of the PELP1 transgene to the mammary gland, we placed the PELP1cyto cDNA under the control of the MMTV promoter. PELP1 transgene integration was verified by PCR and expression levels by Western and IHC in each founder line. Whole-mount preparations and IHC analysis was performed using Tg and age controlled wild type littermates from different developmental stages. Total protein extracts of mammary gland were used for western blot analysis of nongenomic signaling components.&#x2028; Results: Preliminary analysis of mammary gland from PELP-cyto mice showed hyperplasia, increased proliferation as analyzed by PCNA staining. Mammary tumors were observed as early as 32 weeks. No spontaneous mammary tumors were found in the wild type cohort. Pathological analysis revealed that these tumor masses represent full blown mammary adenocarcinomas. Mammary tumors showed excessive activation of nongenomic signaling including activation of Src and AKT pathways. A clear induction of aromatase expression was found in PELP1 tumors compared with the wild-type that showed no aromatase expression in the mammary gland.&#x2028; Discussion: We have established and characterized a transgenic mouse model that mimics deregulated ER-nongenomic signaling. Our results suggest that PELP1 is a proto-oncogene and demonstrates its in vivo tumorigenic potential. PELP1 driven tumors are ER+ve, express aromatase, thus provide an interesting in vivo model for studying ER-mediated tumorigenesis and to study effect of local E2 on ER-mediated tumorigenesis.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 601.