bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-03-05: Triple Negative Breast Cancer: Prognosis Dependent on Presenting Stage Rather Than Receptor Status
Authors: Hamm CM , Poliquin G , Poliquin V , El-masri M. 
Published: April 2011

Abstract
Purpose: To investigate the differences in survival and prognostic factors such as age at diagnosis, stage, size of tumor, mode of identification, treatment and family history between patients that have triple negative breast cancer (TNBC) and those who are not (at least one positive marker).
Methods: a retrospective chart review was conducted on 1018 eligible breast cancer patients who were diagnosed between 2000 and 2005 in Essex, Kent, and Lambton counties in Ontario.
Results: Our demographic findings supported those of previous publications whereby age at diagnosis was younger for TNBC patients (53.2 vs 60.9 respectively; p &lt; 0.001). The frequency of stage III cancer was higher among TNBC patients than that of other cancer patients (16.2% and
6.3%, respectively; p &gt; 0.001). Frequency of self detection was higher among TNBC patients compared to patients with other cancers (76.8% and 56.4%, respectively; p &lt;.001). Perhaps most importantly, while TNBC had had HR of 2.29 (95%CI = 1.33 - 2.93), the adjusted survival analysis suggested that there was no significant difference in the overall survival between the two groups (HR = 1.22; 95%CI = .63 - 2.39). The significant predictors of survival in the adjusted analysis were; age, stage of cancer, and size of cancer.
Conclusions: We believe that this is the first indication that patients with TNBC do as well as their non-TNBC cohorts when matched for stage at presentation. Future studies need to focus on identification of patients who are at increased risk of TNBC so appropriate screening tests can be obtained.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-03-05.
Abstract P5-03-09: Ovarian Hormones Promote Mammary Carcinogenesis by Altering Growth Factor Receptor Signaling
Authors: Arumugam A , Parada J , Gamez M , Boopalan T , Delgado A , Agullo P , Lakshmanaswamy R. 
Published: April 2011

Abstract
Study of carcinogenesis in rat models plays an important role in understanding the nature of neoplastic transformation. Identification of biological, cellular and molecular alterations involved in the carcinogen induced preneoplastic transformation has vital importance in mammary cancer development. Copenhagen rats are resistant to the carcinogen, N-methyl-N-nitrosourea (MNU) induced mammary carcinogenesis. Our previous studies indicate that MNU induced preneoplastic lesions were promoted to mammary cancer by the hormones estrogen and progesterone. The purpose of this study is to delineate the molecular mechanisms of hormonal promotion of mammary carcinogenesis. Seven week old female Copenhagen rats were administered a single dose of 50 mg/kg body weight MNU intraperitoneally. Four weeks post carcinogen administration, rats were divided into 4 groups, 1) Control, 2) rats treated with 30 mg estradiol, 3) rats treated with 30 mg progesterone, 4) rats treated with 30 mg estradiol plus 30 mg of progesterone. Two weeks after the implantation rats were killed and mammary glands were excised and used for further experiments. Quantitative RT-PCR experiments showed up-regulation of growth factor receptors such as Igf-1r, Egfr and growth factor signaling members Grb2, Pi3k and Ras mRNA expression. Immuno histochemical studies showed strong staining to growth factor receptors and western blotting studies showed increased protein levels of growth factor receptors such as IGF-1R and EGFR and active form of proliferative signaling molecules Akt and SAPK/JNK were up-regulated in combination of estradiol and progesterone treated rats. Phosphorylated p38 was reduced in the combination of hormones treated rat preneoplastic lesions when compared to control. Combination of ovarian hormones treatment provided enhanced growth factor signaling environment and promoted the mammary lesions through activation of SAPK/JNK and growth factor signaling pathways.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-03-09.
Abstract P5-06-01: MTA2 and AR Overexpression in ER-Negative Breast Cancer Cells: Roles in Invasion and Metastasis
Authors: Morales SF , Covington KR , Ciupek A , Brusco L , Weigel NL , Lu Y , Mills G , Fuqua SAW. 
Published: April 2011

Abstract
Background: We have previously shown that overexpression of metastasis associated protein 2 (MTA2) can render estrogen receptor (ER)-positive breast cancer cells hormone-independent through postranscriptional effects on ER acetylation and phosphorylation. Recently we discovered that MTA2 overexpression in ER-negative MDA-MB-231 breast cancer cells enhances invasion and metastasis in athymic nude mice which involves activation of the Rho pathway. It is also known that the androgen receptor (AR) is frequently expressed in breast tumors; however its role in proliferation, invasion, or breast cancer metastasis is poorly understood. Materials and Methods: MTA2 was stably overexpressed in MDA-MB-231 and its levels validated using Western blot analysis. To identify downstream effects due to MTA2 overexpression, we employed reverse phase protein arrays, and Affymetrix expression arrays. Significant changes in gene expression were identified using dCHIP software, and student t tests. Invasion was examined using modified Boyden chamber growth assays, proliferation was assayed using soft agar growth and MTT assays, and metastasis was measured as tumor growth in athymic nude mice. Results: MTA2 overexpression in ER-negative cells enhanced distant and skin metastases in athymic nude mice. In an attempt to identify effectors of MTA2-mediated metastasis, we used RNA microarray and protein array screens, and found that AR was significantly increased. As a control, we employed a rescue of the highly metastatic MTA2-MDA-MB-231 cell phenotype via stable transfection and add-back of Rho GDIa, a gene that was concomitantly down-regulated with MTA2 overexpression. AR levels were significantly reduced with Rho GDIa add-back. To determine if AR was functional in these cells, we used ARE-luciferase reporter assays and discovered that both basal, and agonist (R1881)-induced transcriptional activity were significantly enhanced. The AR antagonist, bicalutamide, was effective at significantly decreasing the invasive potential of MTA2- overexpressing MDA-MB-231 cells In vivo experiments in nude mice with bicalutamide treatment are underway.
Discussion: AR was significantly overexpressed with the aggressive phenotype conferred via MTA2 overexpression. This suggests that blockade of AR action might provide a new therapeutic target to inhibit metastasis of breast cancer cells.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-06-01.
Abstract P5-06-10: ErbB Signaling Is Required for Activation of Phosphatidylinositol-3 Kinase and Transformation of Mammary Epithelial Cells by Polyomavirus Middle T Antigen
Authors: Cook RS , Rinehart C , Garrett J , Chakravarti A , Arteaga CL. 
Published: April 2011

Abstract
Summary
Polyomavirus middle T (PyVmT) transforms cells through phosphatidylinositol 3-kinase (PI3K). Overexpression of ErbB2/ErbB3 heterodimers, potent activators of PI3K, occurs in PyVmT-driven mouse mammary tumors, but without known cause and consequence. Inhibition of ErbB2 with lapatinib, or genetically engineered loss of ErbB3, decreased PI3K signaling and tumor growth in mice, suggesting ErbB2/ErbB3 is required by PyVmT. ErbB2/ErbB3 formed signaling complexes containing PyVmT, p85 and Src. EZN-3920, a novel high-affinity oligonucleotide targeting ErbB3 transcripts, impaired ErbB3 expression in vivo, decreased PI3K signaling, cell survival, and growth of tumors, and improved response to lapatinib. Therefore, PyVmT utilizes ErbB2/ErbB3 overexpression to drive PI3K signaling. Furthermore, the challenge of ErbB3 as a kinase-inactive therapeutic target can be overcome by targeting ErbB3 mRNA transcripts in vivo. Significance
Given the widespread use of, and knowledge gained from the MMTV-PyVmT transgenic mouse breast cancer model, understanding how PyVmT utilizes existing cell signaling programs is necessary to interpret how results impact our understanding/treatment of human breast cancers. We found that ErbB2/ErbB3 heterodimers were a necessary part of PyVmT signaling complexes involving Src and PI3K, and that PyVmT depends on ErbB3 in the breast epithelium for PI3K activity and tumor growth. Because ErbB3 harbors a weak/inactive tyrosine kinase, therapeutic anti-ErbB3 interventions present with challenges. Further, anti-ErbB3 antibodies that block ligand interaction with ErbB3 do not alter ligand-independent ErbB3 signaling. However. these challenges were overcome using high-affinity oligonucleotides targeting ErbB3 mRNA. Use of the oligonucleotide EZN-3920 effectively reduced ErbB3 expression, inhibited PyVmT tumor growth, and improved the response of tumors to lapatinib. These results support oligonucleotide knock-down of targets as potential therapeutic strategy.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-06-10.
Abstract P5-10-01: Overall Survival in Breast Cancer Patients in Randomized Controlled Trials Comparing Primary G-CSF Chemotherapy Support to Control
Authors: Lyman GH , Kuderer NM , Crawford J , Culakova E , Poniewierski MS , Huang M , Dale DC. 
Published: April 2011

Abstract
Background Randomized controlled trials (RCTs) have demonstrated that granulocyte colony-stimulating factor (G-CSF) is capable of reducing the risk of neutropenic complications including febrile neutropenia as wellas infection-and treatment-related mortality (Kuderer et al. JCO 2007). To address the potential impact of G-CSF support of chemotherapy on overall survival in patients with breast cancer, a systematic review of RCTs of chemotherapy with or without G-CSF support and at least 2 years of follow-up was conducted.
Methods A systematic review of the medical literature identified 20 RCTs of breast cancer patients receiving chemotherapy with or without primary G-CSF support and reporting overall mortality by study arm. Data extraction from eligible studies was undertaken by two independent reviewers. Heterogeneity was assessed by Cochran's Q-statistic and the Inconsistency Index (I2). Weighted summary estimates of relative risk (RR) with 95% CIs were based on the method of Mantel and Haenszel using a fixed effects model. Planned chemotherapy relative dose intensity (RDI) with G-CSF support compared to control was meta-regressed on the natural logarithm of the RR for mortality. Publication bias was assessed on the basis of Egger's regression intercept.
Results Patients in 20 eligible RCTs received chemotherapy with (n=5,938) or without (n=6,627) primary G-CSF support. Deaths were reported in 1,468 patients randomized to receive primary G-CSF and in 1,607 controls. No significant heterogeneity was observed (Q=23.53, P=.215; I2=19%). Overall RR for mortality was 0.94 [0.89-0.99; P=.029]. RR for mortality was 0.92 [0.85-0.99; P=.036] in the 11 trials of patients with locoregional disease compared to 0.98 [0.92-1.04; P=.503] in the 9 RCTs of patients with advanced disease. A nonsignificant trend was observed between median duration of follow up and RR reduction for mortality [P=.08]. A significant inverse trend was observed between chemotherapy RDI with G-CSF support and RR reduction for mortality [P=.05]. The greatest reduction in mortality was observed in the four RCTs of dose dense chemotherapy. A trend toward publication bias was observed among studies of patients with advanced disease but not locoregional disease.
Conclusions Overall mortality in patients with breast cancer is reduced in those receiving chemotherapy with primary G-CSF support compared to controls. Greater impact on mortality was observed in clinical trials of early-stage disease and in studies with greater chemotherapy RDI including dose dense schedules.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-01.
Abstract P5-10-04: Amplification of Topoisomerase 2 Alpha (TOP2A) in HER2/neu Negative Breast Cancer
Authors: Glynn RW , Mahon S , Miller N , Callagy G , Kerin MJ. 
Published: April 2011

Abstract
Background: TOP2A is of particular interest in breast cancer because of its association with response to anthracycline-based chemotherapies. Much of the work which has examined levels of TOP2A has concluded that amplification is restricted to those who are also HER2/neu amplified, leading some commentators to conclude that HER2/neu negative patients should not receive anthracyclines as part of their treatment. A couple of studies have identified TOP2A alterations in the absence of that of HER2/neu however, and the relationship between these targets needs to be better defined. We aimed to investigate the relationship between HER2/neu and TOP2A, whilst elucidating their association with clinicopathological variables thereby providing further insight into which patients are most amenable to anthracycline-based regimens.
Materials and Methods: Hierarchical clustering was performed on a 20 patient cDNA microarray to identify gene clusters of clinicopathological interest. RQ-PCR was then performed (n=96) to further assess gene amplification, and levels were determined using the comparative Ct approach & Taqman assays. An IHC microarray (n=76) was then employed to check for correlation between gene amplification and protein expression levels.
Results: Amplification levels of TOP2A did not differ significantly according to HER2/neu status by either cDNA microarray (p=0.623), RQ-PCR (p=0.475) or IHC microarray (p=0.736). By RQ-PCR, 14/48 (29.1%) of the HER2/neu negative patients demonstrated levels of TOP2A above the third quartile. Similarly, 11/48 (22.9%) of the HER2/neu positive patients returned values in the first quartile, thereby indicating low-level amplification. Of 60 patients characterised as HER2/neu negative using IHC and FISH, 14 (22.9%) were classified as TOP2A positive on the IHC microarray. Of the 14 patients deemed HER2/neu positive using IHC and FISH, meanwhile, the majority (n=10) were classified as TOP2A positive.
Discussion: Our results indicate that amplification of TOP2A in breast cancer is not confined to those who are concomitantly HER2/neu positive, and suggest that a significant proportion of HER2/neu negative patients exhibit high levels of TOP2A. These findings were not expected, are contrary to popular opinion, and have significant implications in the rationalisation of anthracycline-based therapies.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-04.
Abstract P5-10-10: Benefit of Adjuvant Chemotherapy in Luminal A Breast Cancers
Authors: Heneghan HM , McDermott A , Malone C , McLaughlin R , Sweeney KJ , Kerin MJ. 
Published: April 2011

Abstract
Background:
Perou and Serlie's molecular portraits of breast tumors explain the phenotypic heterogeneity of breast cancers by demonstrating diversity in gene expression, and classify tumors into 5 unique subgroups. The commonest breast cancer intrinsic subtype, Luminal A (ER/PR+, HER2-), generally carries a good prognosis with lower incidence of metastatic spread and longer disease free and overall survival compared to non-luminal tumors. Yet within the Luminal A subgroup there appears to be heterogeneous outcome; and debate continues as to the need for adjuvant chemotherapy within this cohort. In the absence of validated molecular predictors of response to chemotherapy, we aimed to assess the outcomes of a large cohort of Luminal A breast cancer patients in order to determine prognostic factors which may guide future treatment strategies for this subgroup.
Methods:
1355 breast cancer patients treated in a tertiary referral symptomatic breast cancer unit, with known molecular subtype, were identified. 965 had Luminal A primary breast tumors, of whom 57% had received adjuvant chemotherapy. Clinicopathological details of all patients were reviewed, including particular details of the chemotherapeutic regimens administered. Current outcome in terms of disease-free (DFS) and overall survival (OS) was determined. Kaplan-Meir & multivariate analyses were performed to identify tumor/patient characteristics indicative of poor response to adjuvant chemotherapy.
Results:
Mean follow-up was 61.3 months. Overall & disease free survival were significantly better for those who received adjuvant chemotherapy (Mean OS: 60 vs. 54 months, p=0.051. DFS: 54 vs. 44 months, P&lt;0.001). Patients whose disease progressed despite chemotherapy had poorer prognostic indicators at the time of diagnosis, compared to their Luminal A counterparts who remained disease free: including significantly greater tumor size (30.34mm vs. 25.0mm, p=0.01), 69% were node positive and 59.4% had stage 3 or 4 disease (chi square&lt;0.001). Of the cohort of Luminal A patients who remained disease free throughout follow-up, 40% had not received adjuvant chemotherapy. Those women who remained disease free despite not receiving systemic chemotherapy had smaller tumors (26mm vs. 31 mm, p=0.021) were generally postmenopausal (80% vs. 56%, P&lt;0.001) and had predominantly node negative (59% vs. 37%, P&lt;0.001) early stage I and II disease (78% vs. 73%, p=0.001), compared to those surviving women who did get chemotherapy.
Conclusion:
Adjuvant chemotherapy is beneficial in the cohort of Luminal A's with advanced disease at diagnosis. However it is critically importance to identify this particular subgroup & spare those with early disease the toxicity of treatment from which they are unlikely to derive further benefit.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-10.
Abstract P5-10-16: Iodine/Anthracyclines Is the Best Combination Against Mammary Cancer. Antineoplastic Synergism and Cardioprotection
Authors: Alfaro Y , Delgado G , Aceves C. 
Published: April 2011

Abstract
Mammary cancer is the world's most common malignant neoplasia for women. Recently, the mortality for breast cancer has fallen due principally to early detection and to use of neoadjuvant chemotherapy. Anthracycline antibiotics are the most commonly used anticancer drugs, and Doxorubicin (DOX) is the first choice to treat mammary cancer. Nevertheless, its use has limited by its cadiotoxic side effects, which are generated by free radicals. Our studies in methylnitrosourea (MNU)-induced mammary cancer models have shown that supplementation with moderately high doses of molecular iodine (I2) exhibits two distinctive and beneficial effects: antineoplastic and antioxidant. In the present work we explored these dual characteristic of I2 (0.05%) as an adjuvant to DOX16 (therapeutic dose of 16 mg/kg) and DOX8 (8 mg/kg) in female Sprague Dawley rats (200 g) with tumors induced by a single dose of 50 mg MNU per Kg. Iodine intake is initiated 2 days before DOX application and continues up to sacrifice 7 days later. The following parameters were registered: body weight, tumor size, tumor proliferation rate (proliferating cell nuclear antigen, PCNA), serum creatinine kinase-MB activity (CK-MB), cardiac lipoperoxidation (cLPO), and cardiac catalase activity (cCAT). Values correspond to mean± SD. Different superscripts represent significant (p≥0.05). Tumor reduction was greater in the DOX16 + I2 group than in the DOX 16 group (75% vs. 50%, respectively), and was associated with a significantly greater decrease in the rate of tumor cell proliferation (25% vs 10% decrease in PCNA-positive cells), showing the synergistic effect of I2. In contrast, at both DOX doses, the DOX + I2, groups had lower body weight loss and less cardiac damage (CK-MB; 280% vs 100%, cLPO 100% vs 0%) than with DOX alone. cCAT was not changed by any of the treatments.Conclusions: Iodine acts as an adjuvant by significantly enhancing the antiproliferative effect of DOX at a therapeutic dose (DOX16), and it exerts significant general and cardiac protective effects that do not involve catalase activation. Cellular and molecular mechanisms involved in these dual effects of iodine are currently being analyzed. The authors thank Drs. Mauricio Diaz, Marcela Lizano, and Brenda Anguiano as well as Biol. Felipe Ortiz for their technical assistance and Leonor Casanova for academic supports. We also thank Dr. Dorothy Pless for proof-reading. Supported in part by PAPIIT/UNAM 201210 and CONACYT 78955 and 47928/47928. Figure available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-16.
Abstract P5-11-02: The Carry-Over Effect of Adjuvant Zoledronic Acid: Comparison of 48- and 62-Month Analyses of ABCSG-12 Suggests That the Benefits of Combining Zoledronic Acid with Adjuvant Endocrine Therapy Persist Long after Completion of Therapy
Authors: Gnant M , Mlineritsch B , Stoeger H , Luschin-Ebengreuth G , Heck D , Steger G , Jakesz R , Singer C , Eidtmann H , Greil R. 
Published: April 2011

Abstract
Background: ABCSG-12 examined the efficacy of ovarian suppression using goserelin combined with tamoxifen (TAM) or anastrozole (ANA) ± zoledronic acid (ZOL) in premenopausal patients with endocrine-responsive early breast cancer. Results at 48 months and at 62 months show that adding ZOL significantly improved disease-free survival (DFS) and reduced disease recurrence.
Methods: Premenopausal patients with endocrine-responsive early breast cancer (N = 1,803) were randomized to goserelin (3.6 mg q28d) and TAM (20 mg/d) or ANA (1 mg/d) ± ZOL (4 mg q6mo) for 3 years. Endpoints included DFS and overall survival, both analyzed using log-rank test and Cox models.
Results: At 48 months’ median follow-up, ZOL significantly reduced the risk of DFS events by 36% versus no-ZOL (hazard ratio [HR] = 0.64; P = .01); this was maintained at 62 months’ follow-up (HR = 0.68; P = .009). In addition, the trend toward reduced risk of death with ZOL was maintained at both 48 months (HR = 0.60; P = .11) and 62 months (HR = 0.66; P = .10) compared with no-ZOL. Patients receiving ZOL also had fewer distant recurrences compared with no-ZOL: 29 versus 41 events at 48 months, and 44 versus 56 events at 62 months. No significant renal adverse events or confirmed cases of osteonecrosis of the jaw (ONJ) have been reported.
Conclusions: Comparisons of 48- and 62-month data suggest a possible carry-over of the ZOL anticancer benefit 2 years after treatment completion. Additional analyses will be presented, including disease outcomes during therapy and after treatment, as well as overall survival analyses.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-02.