bluuebunny/crossref_metadata_2025_split huggingface dataset:
RAP-011, a soluble activin receptor type IIA IgG-Fc fusion protein, is a novel bone anabolic agent that prevents bone loss and skeletal metastases in a mouse model of metastatic breast cancer.
Authors: Mulivor AW , Barbosa D , Kumar R , Pearsall AE , Underwood KW , Ucran JA , Seehra J , Pearsall R 
Published: December 2010

Abstract
Abstract #1158
Breast cancer cells have a strong propensity to metastasize to bone, resulting in debilitating complications such as intractable bone pain, spinal compression, pathological fractures, or loss of mobility and function. Anti-resorptive agents, such as bisphosphonates, are commonly used to halt the additional loss of bone, but fail to stimulate the formation of new bone to repair lost or damaged bone. Previous data demonstrated that treatment with an activin antagonist, a soluble form of the extracellular domain of the activin type IIA receptor (ActRIIA) fused to a murine IgG-Fc fragment (RAP-011), can restore bone mass in ovariectomized mice with established bone loss and prevent bone loss in a murine model of multiple myeloma.&#x2028; To investigate the ability of RAP-011 to prevent skeletal metastases in an experimental model, bioluminescent breast cancer cells (MDA-MB-231-luc-D3H2LN) were administered by intracardiac injection into athymic nude mice that had been pretreated for 2 weeks with RAP-011 (10 mg/kg S.C. twice weekly) or vehicle (VEH). At 3 and 5 weeks post-inoculation, RAP-011 treated mice displayed lower levels of hind limb, mandible and lung metastases compared to VEH-treated mice. RAP-011 treated mice had reduced tumor burden (-70%) and increased overall survival by 11 days compared to VEH-treated mice. It was also shown that RAP-011 preserved bone mineral density and increased both trabecular volume (BV/TV +140%, P&lt;0.001) and trabecular number (+15%, P&lt;0.001), compared to VEH. In the VEH-treated mice, BV/TV was lower in bones with a tumor present (0.191) than bones without a tumor (0.276, p=0.1). However, RAP-011 treated mice increased BV/TV to a similar extent in both bones with a tumor (0.598) and bones without a tumor (0.599, p=0.98) compared to the VEH controls (p&lt;0.001).&#x2028; Taken together, these data suggest that inhibition of activin has the potential therapeutic benefit of improving bone health in patients with cancer related bone loss as well as preventing metastasis of breast cancer. Towards this end, ACE-011, the human analog of RAP-011, is currently in clinical development for the treatment of cancer-related bone loss.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1158.
A randomized phase 2 trial of low dose (6 mg daily) versus high dose (30 mg daily) estradiol for patients with estrogen receptor positive aromatase inhibitor resistant advanced breast cancer.
Authors: Ellis MJ , Dehdahti F , Kommareddy A , Jamalabadi-Majidi S , Crowder R , Jeffe DB , Gao F , Fleming G , Silverman P , Dickler M , Carey L , Marcom PK 
Published: December 2010

Abstract
Abstract #16
Rationale: It has been postulated that aromatase inhibitor (AI) therapy may sensitize ER+ breast cancer to lower doses of estrogen therapy as second-line endocrine treatment for advanced breast cancer (ABC). We therefore conducted a randomized trial of 30mg generic estradiol daily (10 mg t.i.d.- "recommended" dose) versus 6 mg (2 mg t.i.d - "experimental" dose).&#x2028; Materials and Methods: Major eligibility: Postmenopausal ER+ ABC treated with an AI with 24+ wks progression free survival, or relapse after 2+ yrs of adjuvant AI; RECIST measureable non-bone metastases or WHO assessable bone lesions, with elevated tumor markers &gt;2X ULN. Major exclusions: History venous thrombosis, heart disease, uncontrolled hypercalcemia and fulvestant in the last 12 months. FDG PET scans were conducted at baseline and after 24 hours to assess metabolic flare as a predictor of response (pre-defined as a ≥12% increase in FDG uptake).&#x2028; Results: Sixty-six patients were enrolled (82% White, 15% Black); mean age 59 years, range 36-84. 34 received 6 mg and 32 received 30 mg. Estradiol levels will be provided at the meeting. There were more patients experiencing grade 3+ SAE on the 30 mg arm versus the 6 mg arm (11 vs. 4; P=0.06) with one venous thrombosis on each arm. There was no difference in total FACT-B QOL scores at one month by treatment arm, QOL decline was associated with more severe estrogen side effects, especially amongst patients on the 30 mg arm (P=0.006). Uterine bleeding was successfully controlled with intermittent progestin therapy. Clinical benefit rates (stable disease at least 24 weeks plus response - intent to treat population) were 25% (CI: 15-37%, 1PR and 7SD out of 32) on the 30 mg arm and 29% (CI: 19-42%, 3PR and 7SD out of 34) on the 6 mg arm. Patients with clinical benefit to estradiol could be retreated with original AI after progression and to date one PR out of three patients with repeat AI therapy noted. There were 44 patients evaluable for the interaction between PET -flare and response. Flare was seen in all responders (3/3), 9 of 13 patients with SD and only 3 of 30 patients with PD (p&lt;0.0001). PPV for PET flare was therefore 12/15 (80%, CI: 61-92%) and NPV 27/31 (87%, CI: 76-94%). &#x2028; Conclusions: The Protocol Review and Monitoring Committee closed the 30 mg arm early after they concluded that the 6 mg arm was as effective as the 30 mg arm with greater safety. We therefore recommend 6 mg as the appropriate dose for the palliative treatment of advanced ER+ breast cancer. FDG PET flare can be used to identify patients who have a high chance of clinical benefit.&#x2028; Supported by an AVON NCI Partners in Progress Award: Grant # P30 CA091842-S4.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 16.
Elevated serum levels of the growth factor GP88 are found in breast cancer patients when compared to healthy individuals.
Authors: Serrero G , Tkaczuk K , Zhan M , Tait N , Ilan C , Yue B 
Published: December 2010

Abstract
Abstract #2006
Background: GP88 is an autocrine growth factor that plays a critical role in breast tumorigenesis. GP88 is expressed in human BC tumors in a positive correlation with their tumorigenicity. Increased GP88 expression is associated with resistance to anti-estrogen therapy in ER + cells and with herceptin resistance in Her-2 overexpressing breast tumors. Inhibition of GP88 expression in human breast adenocarcinoma inhibited tumor incidence and growth in nude mice. Immunohistochemical studies have shown that GP88 was expressed in invasive ductal carcinomas in correlation with the expression of poor prognosis markers whereas normal tissues and benign lesions were negative. High GP88 expression in tumor biopsies was accompanied by decreased disease-free survival. Since GP88 can be secreted, we have hypothesized that GP88 could be secreted in the circulation and found in serum. We examined whether GP88 could be found in the circulation and whether GP88 could be elevated in the sera of breast cancer patients when compared to healthy individuals.&#x2028; Methods: An IRB approved blood sampling study was conducted at the University of Maryland Breast Clinic to determine the serum level of GP88 in healthy volunteers (HV) and breast cancer patients (BC pts). Serum GP88 concentration was determined in triplicate by quantitative enzyme immunoassay. 189 BC pts were accrued. In addition, sera from 18 HV were obtained to establish a GP88 baseline in healthy volunteers. BC patient characteristics: Race: Caucasian- 91, African American-92, Asian-6; median age, 51 (range 29-86), stage I – 48, II - 52, III – 26, IV - 63.&#x2028; Results: Circulating GP88 was measurable in the serum. Median level of GP88 was 28.7 ng/ml (range 16.6-38.2) in HV; 40.7 ng/ml (range 6.4-100) in early stage (stage 1 –3) BC pts (p- value = 0.007) and 45.3 ng/ml (range 9.8 to 158.4) in stage 4 metastatic BC patients (p-value= 0.0007). Statistically significant increase in circulating GP88 level was found in early stages as well as in metastatic disease. Correlation studies with BC prognostic factors such as stage, tumor size, lymph node involvement, tumor grade and presence of ER and HER-2 will be presented.&#x2028; Conclusion: GP88 can be detected in the sera of HV and BC pts. Comparison between the two groups of subjects indicates that GP88 level is significantly higher in the sera of BC pts. These studies are important as they identify as a measurable circulating biomarker GP88 that is also a therapeutic target of malignant transformation or malignant progression of breast carcinoma (BC). Future studies will examine whether there is any correlation between the serum level of GP88 and therapeutic response to systemic therapy in breast cancer patients.&#x2028; This study was supported by grant from MIPS, the Avon Foundation and 1R43 CA 124179-01A1 from the National Institutes of Health.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2006.
Role of radiation induced ß1 – integrin expression in trastuzumab resistance in Her-2 positive breast cancer.
Authors: Thoms J , Sabri S , Lesniak D , Murray D , Abdulkarim B 
Published: December 2010

Abstract
Abstract #2014
Problem Statement: Radiation therapy followed by Trastuzumab-based therapy is the standard of care for Her-2 positive breast cancer (BC) patients, but the molecular basis of this sequential treatment has not been investigated. Fifty percent of early BC patients show primary resistance to Trastuzumab (Tz) and 70% of metastatic breast cancer patients develop Tz resistance within one year. Our in vitro pre-clinical data suggests the role of ß1-integrin, a cell adhesion molecule involved in cell survival, invasion and drug resistance, in Tz resistance. Because ionizing radiation (IR) increases the expression of several integrin subunits in endothelial and tumor cells, we hypothesized that radiation induced ß1-integrin expression could be a potential mechanism of Tz resistance in Her-2 positive BC patients.&#x2028; Methods: We use Her-2 positive Tz-senstive BC cell lines, SKBR-3 and BT474, which express lower levels of ß1- integrin, than the Tz-resistant cell line JIMT-1.&#x2028; We analyzed by Immunoblotting the expression of ß1-integrin, phosphorylation and expression of Her-2 and common downstream signaling pathways, PI3-K/Akt and Erk1/2 before and after exposure to IR.&#x2028; Results: Exposure to IR increased ß1-integrin expression in SKBR-3 and BT474 cells, but not in JIMT-1. Increased ß1-integrin expression in BT474 cells was associated with a substantial increase in phosphorlyation of Her-2, suggesting that ß1-inetgrin may induce transactivation of Her-2. Phosphorylation of Erk 1/2 and Akt, important signal transducers for cell proliferation and survival were also increased.&#x2028; We will further, investigate Tz sensitivity of SKBR-3 and BT474 following exposure to IR using a blocking antibody for ß1-integrin, and clonogenic survival and XTT assays to evaluate cellular viability and proliferation.&#x2028; Conclusion: Our results show that IR increased ß1-integrin expression and activation of the PI3-K/Akt pro-survival pathway and suggest that increased b1-integrin expression by IR may confer resistance to Trastuzumab in Her-2 positive cell lines. The physiological relevance of radiation-induced ß1-inetgrin expression in Trastuzumab resistance needs to be further investigated in vivo.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2014.
Tissue inhibitor of metalloproteinases-1 protects the human breast carcinoma cell line MCF-7 S1 against anthracycline-induced cell death by activation of the akt survival pathway.
Authors: Würtz S[ , Schrohl A , Brünner N , Lademann U 
Published: December 2010

Abstract
Abstract #2019
Würtz S and Schrohl A contributed equally.&#x2028; Background. A large proportion of breast cancer patients are offered chemotherapy following primary surgery, however, many of these patients do not benefit from the treatment. Currently, only few markers exist to predict whether a breast cancer patient will respond to chemotherapy in general or to specific types of chemotherapy. Thus, additional predictive markers need to be identified to ensure a more effective treatment of the patients. In this regard, recent clinical studies performed in our laboratory have demonstrated that high tumor tissue levels of TIMP-1 are associated with a poor response to the most frequently used chemotherapeutic drugs (CMF or anthracyclines) (Schrohl et al., Clin. Cancer Res. 2006 and Klintman et al. manus. in prep.). The purpose of the present study was to investigate the molecular explanation for the clinical findings concerning the predictive value of TIMP-1 using an in vitro approach.&#x2028; Methods. We stably transfected the human breast carcinoma cell line MCF-7 S1 with the human TIMP-1 gene and established single cell clones expressing different levels of TIMP-1. We then compared the sensitivity of these cells to epirubicin and taxol using cell death and apoptosis assay. In addition, we investigated the signalling pathway that could be involved in the TIMP-1 mediated protection against treatment using western blotting of key molecules.&#x2028; Results. We found that clones expressing high levels of TIMP-1 were significantly less sensitive to epirubicin. In contrast, no difference in sensitivity to taxol was demonstrated between high and low TIMP-1 clones. When investigating the signalling pathway involved in the difference in sensitivity we found that phosphorylated Akt was highly up-regulated in the high TIMP-1 clones compared to the low TIMP-1 clones following chemotherapeutic treatment.&#x2028; Conclusion. TIMP-1 protects the MCF-7 S1 cells against anthracycline-induced cell death but not against taxol. Thus, TIMP-1 may be used to discriminate between patients likely to benefit from anthracyclines and patients who should be offered an alternative drug. Furthermore, we found that this protection is probably executed through counteraction of the apoptotic signal by activation of the Akt survival pathway.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2019.
Sentinel node biopsy performed in the neoadjuvant setting for breast cancer: results from the I-SPY TRIAL (CALGB 150007/150012 & ACRIN 6657).
Authors: Gomez RE , Zakhireh J , Moore D , DeMichele A , Przewoznik J , Ollila D , Frank J , Krontiras H , Montgomery L , Sarode V , Broadwater G , Esserman L , Network the I-SPY TRIAL 
Published: December 2010

Abstract
Abstract #202
Introduction: Controversy remains over whether to perform sentinel node biopsy (SNB) before or after neoadjuvant chemotherapy (NAC). We examined the practice patterns, feasibility, and accuracy of this procedure in high risk breast cancer patients treated with NAC in a multi-institutional correlative science study.&#x2028; Methods: Patients with biopsy-proven breast cancer &gt;3 cm enrolled into the I-SPY TRIAL to undergo 4 weeks of anthracycline-based NAC, 4 weeks of taxane treatment, then surgical intervention. Study protocol did not dictate axillary treatment. Timing of SNB was dictated by the surgeon. Practice patterns, outcome of SNB and axillary lymph node dissection (ALND), locoregional recurrence and distant metastases were recorded with a mean follow-up of 2.9 years.&#x2028; Results: 237 patients enrolled, 221 completed the trial, 210 had complete data at the time of analysis; Table 1 shows axillary practice patterns.&#x2028; &#x2028; Overall, 43% had a positive SNB and/or ALND after NAC. 129 (61% of 210) patients presented with clinically positive nodes, 39 of which had a post-NAC SNB. 5/39 had no ALND (all SNB negative). Table 2 shows results for those who had a post-NAC SNB and ALND. For this subset of patients, sentinel node ID, accuracy, and false negative (FN) rates were 80%, 91% and 15% respectively. If SNB was negative, 20% of patients still had a positive ALND. 81 (39% of 210) patients presented with clinically negative nodes, 22 of which had a post-NAC SNB. 8/22 post-NAC SNB patients had no ALND (6 negative, 2 positive for 1mm disease). Table 2 shows results for those who had a post-NAC SNB and ALND. For this subset of patients, sentinel node ID, accuracy, and FN rates were 100%, 100% and 0%.&#x2028; &#x2028; Overall, there were 26 deaths; 96% occurred in those who presented with clinically positive nodes, 77% had positive post-NAC nodes. A negative axilla post-NAC was predictive of longer DFS over those with axillary disease post-NAC (p&lt;0.05).&#x2028; Conclusions: In clinically node negative patients, post-NAC SNB is feasible and accurate before or after NAC. Our data suggests that a post-NAC SNB is sufficient; this avoids an additional operation and allows us to gain information on post-NAC axillary status which is of prognostic significance. In clinically positive patients, SNB does not adequately reflect axillary disease; even when SNB was negative, 20% still had axillary disease. At this time, we recommend that ALND be performed on all clinically node positive patients.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 202.
Chromosome translocations and fusion genes in breast cancer.
Authors: Howarth KD , Batty EM , Beavis JC , Blood KA , Newman S , Ng B , Pole JC , Chua Y , Ichimura K , Collins VP , Project CG , Chin S , Caldas C , Carter NP , Edwards PA 
Published: December 2010

Abstract
Abstract #2021
Background: Little is known about chromosome translocations in the common epithelial cancers such as breast cancer, in spite of the central role played by translocations and consequent gene fusions in haematopoietic cancers.&#x2028; Methods: We present a comprehensive analysis by array painting of the chromosome translocations of four breast cancer cell lines, DU4475, HCC1806, HCC1187 and ZR-75-30. In array painting chromosomes are isolated by flow cytometry, amplified and hybridized to DNA microarrays. All breakpoints, totalling nearly 250, were mapped to at least 1Mb resolution and most balanced breakpoints were mapped to about 2kb resolution using custom oligonucleotide arrays. The remaining unbalanced breakpoints were mapped to around 20kb by identifying copy number steps in Affymetrix SNP6 array hybrizations obtained by the Sanger Institute's Cancer Genome Project. Breast tumours in parraffin section in tissue microarrays were screened by FISH to see whether selected breakpoints found in the cell lines are present in breast tumours.&#x2028; Results: We found at least 12 reciprocal translocations in the four cell lines, substantially more than expected, and many more rearrangements were balanced for at least one participating chromosome. Many of the breakpoints were within or adjacent to cancer-relevant genes, and three of the translocations have already been shown to form fusion transcripts, RIF1-PKD1L1, PUM1-TRERF1 and TAX1BP1-AHCY. For selected genes targetted by the translocations, about 100 breast tumours were screened for breaks. Breaks were found in two to six cases for several of the genes, confirming that some of them were broken in breast tumours. For example two cases of unbalanced breakage were identified in PKD1L1, and these were confirmed by array-CGH.&#x2028; Discussion: Our results suggest that breast cancers have fusion genes, and support the emerging view that chromosome rearrangements are likely to play a significant role in common epithelial cancers.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2021.
The pattern of metastatic spread among breast cancer sub-types.
Authors: Kennecke HF , Yerushalmi R , Woods R , Cheang M , Voduc D , Speers C , Nielsen T , Gelmon K 
Published: December 2010

Abstract
Abstract #2025
Background: Although breast cancer subtypes are associated with differing relapse risks, the patterns of metastatic spread are less well defined, particularly for more than the first site of metastasis. We describe the sites of all diagnosed metastases among breast cancer subtypes in a large series of women diagnosed with breast cancer to further define patterns of spread.&#x2028; Methods: Subjects with early stage breast cancer referred to the British Columbia Cancer Agency from 1986 to 1992 were included. Archival paraffin tissue blocks were used to construct a tissue microarray. Breast cancer subtypes were defined as Luminal A (ER/PR+ and HER2- and Ki67 &lt;19%), Luminal B (ER/PR+, and HER2- and Ki67 &gt;19%), LuminalHer2 (Her2+ and ER/PR+), HER2 (HER2+ and ER- and PR-), and Basal (HER2-ER-PR- and CK 5/6+and/orEGFR+). All documented sites of distant metastasis were abstracted by chart review according to predefined categories.&#x2028; Results: 3526 eligible women were classified according to Luminal A (2109), Luminal B (514), LuminalHER2 (252), HER2 (276) and Basal (375) and 30%,47%, 48%, 50% and 42% in each subgroup were diagnosed with distant metastasis. Median Survival with metastatic disease was 2.2, 1.6 and 1.3 years in Luminal A, B and LuminalHER2 groups and 0.7 and 0.5 years in the HER2 and Basal types, respectively. Bone was the predominant site of metastasis for luminal groups A (76%), B (73%) and LuminalHER2 (70%). The distribution was more heterogeneous in HER and Basal groups. High rates of brain metastasis were observed in the HER2 (30%) and Basal (27%) and less frequently in the LuminalHER2 (17%) and other groups (p &lt;0001).&#x2028; &#x2028; Conclusion: Molecular breast cancer subtypes are associated with specific distributions of metastasis which may lead to specific prophylactic therapies to modify this risk. New systemic therapies, including trastuzumab, may impact these patterns and survival after recurrence.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2025.