bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-15-07: Late Toxicity and Patient Self-Assessment of Breast Appearance/Satisfaction on RTOG 0319: A Phase II Trial of Three Dimensional Conformal Radiation Therapy (3DCRT) Partial Breast Irradiation (PBI) Following Lumpectomy for Stage I and II Breast Cancer
Authors: Chafe SJ , Moughan J , Vicini FA , Wong JWC , Pass HA , Rabinovich RA , Arthur DW , Petersen IA , White JR , McCormick B. 
Published: April 2011

Abstract
Background:
Ongoing phase III trials are comparing accelerated PBI around the lumpectomy site to standard whole breast irradiation in early stage breast cancer. Recent studies have questioned the late toxicity from PBI delivered with 3DCRT. We evaluated late toxicity on patients (pts) treated on RTOG 0319.
Methods:52 pts with stage I-II breast cancer, ≥3 cm, negative margins, and &lt; 3 nodes positive were treated with 3DCRT PBI and received 38.5 Gy in 10 BID fractions over 5 days. Median follow-up was 5.3 years (min-max: 1.7-6.4 years). Five pts were deceased at 5 years. NCI CTCAE v3.0 was used to grade adverse events (AEs). At 3 years, 50 pts were available for AE reporting or late toxicity assessment.
Results: The treatment-related AEs were primarily grade 1 36.5%, 50% grade 2, and only 3 (5.8%) pts had grade 3 AEs. The grade 3 AEs in these pts were radiation dermatitis, skin fibrosis, telangectasia, and myositis. No baseline self-assessment of breast appearance is available. Patient self-assessment of breast appearance and satisfaction was available in 45 (87%) pts at 1 year and 36 (72%) at 3 years. At 1 year, 82% self reported excellent/good breast appearance and at 3 years, 64%. Pts who reported &lt; excellent/good breast appearance had significantly more grade ≥2 skin AEs (telangectasia, skin atrophy, hyperpigmentation, erythema, skin fibrosis, radiation dermatitis, and breast or nipple/areolar deformity). At 3 years, 31 of 36 pts were satisfied with their treatment, but all 36 would choose 3DCRT PBI again over standard breast RT. Treatment factors were evaluated to establish correlation with patient reported breast appearance. Preliminary observations suggest surgical bed volume, PTV volume, number of beams used, and possible use of bolus are associated with patient reported outcomes (PRO). Surgical factors impacting PRO were not collected.
Conclusions: The majority of pts were satisfied with their treatment results at 3 years and would all choose to have 3DCRT PBI again. With a median of 5.3 years, the rate of grade 3 AEs is low. Technical factors from this phase II trial were modified for the phase III NSABP B-39/RTOG 0413 trial, in which bolus is not allowed and both target volumes and required coverage were modified, increasing expectation of improved PRO. Supported by RTOG U10 CA21661, CCOP U10 CA37422 and ATC U24 CA 81647 NCI grants.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-15-07.
Abstract P4-01-05: Lapatinib Resistance Confers Cross-Resistance to Microtubule Inhibitors in ErbB2-Overexpressing Breast Cancer Cells
Authors: Araki K , Gallas M , Liu X , Jegg A-M , Ward T , Pegram M. 
Published: April 2011

Abstract
ErbB2 gene amplification occurs in approximately 20% of all breast cancers and is associated with an aggressive subtype with poor clinical prognosis. Acquired resistance to erbB2-targeted therapies is a common occurance even in patients who show an initial clinical response to trastuzumab or lapatinib-based regimens. Optimal treatment for relapsed disease following erbB2 targeted therapies has not been defined. Therefore, we sought to evaluate whether cytotoxic agents have cross-resistance to lapatinib in cell lines that have acquired resistance to lapatinib. Here we established a model of acquired lapatinib resistance derived from erbB2 overexpressing breast cancer cell lines, BT474 and SKBR3. Lapatinib resistant cell lines, BTLapR and SKLapR, were generated by growth in the continuous presence of 2.6 uM lapatinib (peak plasma concentration in human subjects) resulting in IC50 of 4.72 uM (BTLapR) and 0.083 uM (BT474) (P&lt;0.0001). IC50 of SKLapR and SKBR3 were 17.72 uM and 0.1637 uM (P&lt;0.0001), respectively. Next, resulting cells were treated with different classes of chemotherapeutics (2 taxanes, 2 vinca-alkaloids, 1 epothilone, 1 anthracycline, 1 antimetabolite, 2 platinums, and 1 alkylating agent) in order to address cross-resistance to lapatinib. BT474 and BTLapR as well as SKBR3 and SKLapR were exposed to each chemotherapeutic agent and cell viability was evaluated at 72h using a cell proliferation assay (AlamarBlue®). We found that BTLapR was significantly cross-resistant to 5 microtubule inhibitors (paclitaxel, docetaxel, vinorelbine, vinblastine, and ixabepilone), but SKLapR was not (shown in table below).
IC 50 of Significant Drugs on Lapatinib Resistant BT474 cells
Previous studies have shown that resistance to lapatinib can switch cell survival signaling from the erbB2 to ER pathway, and that ER signaling can stimulate beta III tubulin expression. We therefore hypothesize the differential responses to microtubule inhibitors in BTLapR and SKLapR might be explained by the fact that BT474 has both estrogen (ER) and progesterone receptor (PR), but SKBR3 express neither. Moreover, beta-III tubulin is known to be a key resistance mechanism of microtubule inhibition. Western blot analysis of baseline protein expression in both acquired lapatinib-resistant and parental cells indicates that ER signaling is involved in stimulating beta III tubulin and is linked to the development of resistance to microtubule inhibitors. These findings point to a potential mechanism to address cross resistance between lapatinib and microtubule-interacting agents, which could have potential clinical implications when considering salvage therapies following lapatinib treatment.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-01-05.
Abstract P4-02-04: Impact of CYP2D6 Genotype and Side-Effects on Adherence Rates to Tamoxifen in Premenopausal Breast Cancer Patients
Authors: Hubalek M , Oberguggenberger A , Meraner V , Beer B , Giesinger J , Oberacher H , Sperner-Unterweger B , Marth C. 
Published: April 2011

Abstract
Background: Only few studies have investigated the issue of breast cancer patients’ adherence to tamoxifen therapy and factors influencing adherence behavior. Especially in the context of different CYP2D6 genotypes adherence to tamoxifen has not been extensively studied yet. Variations in the CYP2D6 genotype, as well as patients taking inhibitors of CYP2D6 (e.g. antidepressants) contribute to different side effects and adherence rates to adjuvant tamoxifen.
Materials and Methods: 106 premenopausal breast cancer patients who met inclusion criteria were consecutively included in the study at the outpatient unit of the Department of Gynecology, Innsbruck Medical University. Within their routine after care appointment patients completed a comprehensive PRO assessment including the FACT-B/ES, the HADS and a self-report questionnaire on adherence behavior (SMAQ). The multi-method approach comprised the Simplified Medication Adherence Questionnaire, a semi-structured interview, physicians’ ratings and blood levels for tamoxifen metabolites. Additionally, the CYP2D6 genotype was determined in all patients participating in this part of the study.
Results: 19% patients were poor metabolizer (PM), 51% intermediate metabolizer (IM), 29% extensive metabolizer (EM) and 7% ultra-rapid metabolizer (UM). Significant group differences with regard to tamoxifen and endoxifen serum concentrations were found between the metabolization groups (p=0.044). UMs had the lowest tamoxifen and highest endoxifen concentrations. Only 3.2% of the patients analyzed had no measurable tamoxifen concentrations in their serum. All non-compilant patients were from the extensive metabolizer group. However, during follow-up 25% (2/6) of patients with UM genotype, 13% (4/30) with EM genotype, 1% (1/50) with IM genotype and 0% (0/19) with the PM genotype discontinued their tamoxifen therapy due to therapy related side effects. In addition anti-depressants were more frequently prescribed in the extensive metabolizer group leading to lower levels of the active metabolite endoxifen. Conclusion: A trend towards higher hot flashes was observed in the EM and UM group. We did not find significant differences in QOL between
CYP2D6 metabolizing groups. Trend level significance was found for global QOL (on a descriptive level) physical well-being and emotional well-being. Non-adherence to tamoxifen therapy is more frequent in patients with CYP2D6 EM and UM genotype. These preliminary data may explain part of the current controversy over CYP2D6 genotype predicting response to tamoxifen and suggest that patients most likely to benefit from tamoxifen are paradoxically most likely to stop their tamoxifen therapy prematurely.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-04.
Abstract P4-02-08: STAT Signaling in Endocrine Sensitive and Resistant Breast Cancer — A Potential Target for Therapy?
Authors: Huang R , Faratian D , Harrison DJ , Langdon SP. 
Published: April 2011

Abstract
The STAT (for signal transducer and activators of transcription) family of molecules regulate cell growth, survival, and differentiation as important integrators of cytokine and growth factor receptor signaling. STAT3 and STAT5 have been implicated in endocrine resistance in breast cancer. We aimed to identify new modifiers of endocrine sensitivity in breast cancer using functional proteomic profiling of the estrogen/tamoxifen-sensitive MCF-7 cell line and its partially sensitive (LCC1) and fully resistant (LCC9) variants. Using an unsupervised analysis of the expression of 125 paired phosphorylated and non-phosphorylated epitopes in key oncogene and tumour suppressor pathways on antibody arrays, STAT1, STAT3, and their phosphorylated epitopes were differentially expressed between endocrine resistant and parental controls. Differential expression was confirmed by qRT-PCR and western blotting. The STAT1 inhibitor EGCG inhibited cell number in endocrine insensitive and resistant LCC1/LCC9 lines, while the STAT3 inhibitors static and WP1066 were equally effective in endocrine-resistant and parental lines. Reduction in cell number was shown to be due to induction of apoptosis rather than inhibition of proliferation. The effects of the STAT inhibitors were additive, rather than synergistic, when tested in combination with tamoxifen in vitro. Finally, expression of STAT 1 and STAT3 were measured by quantitative immunofluorescence in 54 invasive breast cancers and expression levels of STAT1 and STAT3 transcript analysed in 550 breast cancers from publicly available gene expression datasets (GSE2990, GSE12093, GSE6532). High expression of STAT1, and low expression of STAT3, were associated with a worse distant metastasis free survival (DMFS; RR 1.42 and 0.46; log-rank p=0.042 and P&lt;0.0001, respectively). When treatment with tamoxifen was considered, STAT1 expression was nearly predictive of DMFS (log-rank p=0.067), while STAT3 expression was predictive of DMFS (log-rank P&lt;0.0001). These results suggest that STAT signaling may be important in endocrine resistance, and that STAT inhibitors, particularly STAT1 inhibitors, may be effective therapies in breast cancer even in the resistant setting.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-08.
Abstract P4-02-15: Overlapping Therapy with High-Dose Tamoxifen and CYP2D6 Inhibitors Modifies Medication Adherence in Breast Cancer Patients
Authors: Markward NJ , Tinnirello J , Khalid M , Frueh FW , Milayna S , Aubert RE , Epstein RS. 
Published: April 2011

Abstract
Background: Tamoxifen is a selective estrogen receptor modulator (SERM) commonly used to treat and prevent estrogen-receptor-positive (ERP) breast cancer. However, despite its established efficacy, recent studies indicate that 1 in 2 patients will discontinue use of the drug prior to completing the recommended five-year treatment cycle. The alleviation of unpleasant side effects through personalized targeting of tamoxifen dose and, as appropriate, concomitant administration of a CYP2D6 inhibitor could increase adherence and increase the likelihood that patients will receive the amount of the drug needed to protect them against disease onset and/or recurrence. Materials and Methods: A retrospective cohort study was implemented to assess whether overlapping therapy with highdose tamoxifen and CYP2D6 inhibitors influence medication adherence during the first 540 days of therapy. Subjects (N = 17,242) were identified in an integrated medical and pharmacy claims database and selected for inclusion in the study if they 1) filled a new tamoxifen prescription between 7/1/2008 and 6/30/2009 and 2) were continuously eligible to receive pharmacy benefits during the 6 months preceding and 12 months after initiation of therapy. Eligible participants were then cross-classified according to tamoxifen dose (NORMAL, HIGH) and CYP2D6 inhibitor status (NO, YES), and a Cox regression model was fitted to the data to obtain covariate-adjusted hazard ratios (HR) and 95% confidence intervals for each treatment combination relative to the HIGH/NO group.
Results: The lowest and highest hazard ratios were observed in the NORMAL/YES [HR = 0.924 (0.88, 0.97)] and HIGH/NO [HR = 2.33 (2.07, 2.62)] categories. Moreover, the risk of discontinuation was significantly reduced when high-dose tamoxifen was administered in concert with a CYP2D6 inhibitor [HR = 1.31 (0.953, 1.802)]. Discussion: These study suggests that joint treatment with high-dose tamoxifen and a CYP2D6 inhibitor may improve tamoxifen adherence in breast cancer patients. The findings also highlight the need for 1) education and research regarding tamoxifen dosing and 2) careful consideration for when–and under what circumstances–concomitant medications should be prescribed to enhance patient tolerance of tamoxifen-related negative symptoms.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-15.
Abstract P4-05-05: Stromal Response to 14-Day Preoperative Therapy in Postmenopausal Oestrogen Receptor Positive Breast Cancer
Authors: Lo C , Busch S , Lee AG , Searle G , Lamb R , Cramer A , Winter MC , Coleman RE , Dixon M , Bundred NJ , Landberg G. 
Published: April 2011

Abstract
Background: Stromal-epithelial interaction is a key factor in tumour progression. Cancer-associated fibroblasts (CAFs) and macrophage infiltration have been associated with early relapse in breast cancer. Bisphosphonates are effective inhibitors of osteoclast activation in metastatic breast cancer but also have a general inhibitory effect on breast cancer progression. In order to monitor a potential tumour stromal response in breast cancer during treatment with an aromatase inhibitor and a bisphosphonate we analysed pre-and post-treatment samples from a neoadjuvant window study and focused on the presence of macrophages and CAFs.
Materials and methods: Tissue microarrays (TMAs) from surgical samples and pre-operative core biopsies were immunohistochemically stained for aSMA (CAF marker), CD68 (macrophages) and epithelial proliferation (Ki67). In order to validate if the presence of macrophages and aSMA could be monitored by the TMA approach, we initially analysed a screening cohort of 144 breast cancer samples. We then studied pre-and post-treatment samples from 110 postmenopausal ER-positive invasive breast cancer patients randomised to receive 14 days of preoperative treatment (placebo, Letrozole, or Letrozole plus Zoledronate). Results: In the screening cohort, we observed significant links between aSMA positive fibroblasts and disease recurrence as well as between CD68 positive macrophages and tumour size, grade, lymph node positivity and recurrence. This validated the use of TMAs for stromal analyses and furthersupported a link with key tumour biological events. In both treatment arms, there was a significant drop in absolute Ki67 value compared to placebo (-9.3% Letrozole and -13.1% combination reduction versus 1% increase, P&lt;0.001). Post-treatment CD68 (median 35, range 3 to 117) was significantly linked to a Ki67 drop (p=0.045). Interestingly, this effect was mainly observed in the combination treatment group (p=0.002). aSMA expression was unaffected during treatment in 52%, increased in 35% and decreased in 13% of cases. Patients with aSMA reduction post treatment had a larger Ki67 fall compared to patients with increase or no change in aSMA (p=0.007).
Conclusion: Short term treatment response in the epithelial component of cancers was paralleled by specific responses in the tumour stromal component. These novel findings suggest that bisphosphonates and aromatase inhibitors have major effects on tumour stroma in vivo which might augment their inhibitory effect on tumour progression.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-05-05.
Abstract P4-06-12: The Urokinase-Type Plasminogen Activator Is a Direct JAG1- Mediated Notch Target in Breast Cancer
Authors: Reedijk MJ , Shimizu M , Cohen B , Goldvasser P , Berman H , Virtanen C. 
Published: April 2011

Abstract
Aberrant activation of the Notch signaling system and over-expression of the Notch ligand JAG1 are associated with poor outcome in breast cancer. The plasminogen activator system, which includes urokinase-type plasminogen activator (uPA), has been validated as a marker of recurrence, high metastasis risk and death in breast malignancy. By using microarray profiling of breast cancer cell lines that had undergone siRNA-mediated abrogation of Notch signaling we uncovered a link between activated Notch and uPA expression. An association between elevated expression of the Notch ligand JAG1, uPA and the basal breast cancer subtype was confirmed in breast cancer cell lines. The association between JAG1 and uPA expression persisted in a survey of primary carcinomas of the breast. We found that Notch knockdown reduced transcription of uPA and phenocopied uPA knockdown in breast cancer cells. Through mutational analysis we identified a CBF-1 binding site in the uPA promoter that is required for direct transcriptional regulation by Notch. These data suggest that JAG1-induced Notch activation results in breast cancer progression through up-regulation of the plasminogen activator system and directly links these two poor prognosis pathways.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-12.
Abstract P4-06-14: Induction of Blimp-1 in Breast Cancer Cells Is Mediated by Activator Protein-1 and Promotes Transforming Growth Factor (TGF)-ß-Induced Epithelial-to-Mesenchymal Transition
Authors: Romagnoli M , Belguise K , Wang X , Sonenshein GE. 
Published: April 2011

Abstract
The vast majority of breast cancers has been shown to display aberrant constitutive expression of NF-kB subunits, which enhances their mobility and promotes their survival and malignancy. Recently, we demonstrated that the RelB NF-kB subunit promotes migration of breast cancer cells, in part via repression of estrogen receptor (ER)α transcription. Furthemore, we showed that inhibition of the ERα promoter was mediated by the zinc finger transcriptional repressor B lymphocyte-induced maturation protein (Blimp-1), transcribed from the PRDM1 gene, which is induced by RelB-mediated activation of a Bcl-2/Ras pathway. Indeed, we showed for the first time that Blimp-1 is present in breast cancer and is more highly expressed in ERα negative breast cancer cells where it plays an essential role in their migratory and invasive abilities. Blimp-1 is a well-known zinc finger repressor, which is critical for terminal differentiation of B and T cells and for migration of primordial germ cells. Here we have examined the mechanism of activation of Blimp-1 expression in breast cancer cells. Given the role of Ras to c-Raf signaling in migration of cancer cells, we tested the role of this downstream mediator. A constitutively active c-Raf led to induction of Blimp-1 in breast cancer lines while a dominant negative variant reduced its levels. RelB/p52 NF-kB complexes induced c-Jun, c-Fos, Fra-1 and Fra-2 Activator Protein-1 (AP-1) subunits, which activated the PRDM1 gene promoter. The transforming growth factor (TGF)-β induces a more mesenchymal phenotype of breast cancer cells. Treatment of NMuMG breast epithelial cells with TGF-β led to Blimp-1 activation through AP-1 and epithelial-to-mesenchymal transition (EMT). Importantly, Blimp-1 knockdown counteracted TGF-mediated EMT and wound healing in both NMuMG and MDA-MB-231 breast cells. Thus, activation of AP-1 complexes via a Ras/Raf/Erk signaling pathway mediates induction of PRDM1 gene transcription and Blimp-1 expression in ERα negative breast cancer cells, which is essential for TGF-β-induced mesenchymal phenotype. Therefore, downstream mediators of Blimp-1 activity might emerge as new therapeutic targets for treatment of patients with ERα negative breast cancer.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-14.
Abstract P4-06-21: Matrix Metalloproteinase 2 in Tumor Cell-Induced Platelet Aggregation: Regulation by Cryptotanshinone
Authors: Linggeng Y , Yin L , Chenhu H , Junshan R , Lei Z , Li T. 
Published: April 2011

Abstract
Background: A correlation exists between the ability of tumor cells to aggregate platelets and their tendency to metastasize. Tumor cell-induced platelet aggregation (TCIPA) facilitates the embolization of the vasculature with tumor cells and the formation of metastatic foci. It is well documentedthat matrix metalloproteinases (MMPs) play an integral part in tumor spread and the metastatic cascade.
Material and Methods: Therefore, we have examined the role of MMPs during TCIPA and its regulation by Cryptotanshinone in vitro. Human breast cancer cell line MCF-7 and MDA-MB-231 induced TCIPA in a concentration dependent manner that was monitored by aggregometry. This aggregation resulted in the release of MMP-2 from platelets and cancer cells, as measured by RT-PCR.
Results:MCF-7 cells released significantly more MMP-2 than MDA-MB-231 cells and were more efficacious in inducing TCIPA. Inhibition of MMP-2 with phenanthroline (1-1000 mM), a synthetic inhibitor of MMPs, and by neutralizing anti-MMP-2 antibody (10 mg/ml) reduced TCIPA induced by MCF-7 cells. TCIPA was abolished by simultaneous inhibition of platelet function with acetylsalicylic acid (100 mM; thromboxane pathway inhibitor), apyrase (250 mg/ml; ADP pathway inhibitor), and phenanthroline. Cryptotanshinone inhibited TCIPA and MMP-2 release from platelets and tumor cells.
Discussion:We conclude that (a) human Human breast cancer cells aggregate platelets via mechanism (s) that are mediated, in part, by MMP-2; (b) Cryptotanshinone inhibits TCIPA, in part, by attenuating the release of MMP-2.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-21.