bluuebunny/crossref_metadata_2025_split huggingface dataset:
P4-17-06: Prognostic Role of Triple Negative Subtype in Breast Cancer Patients with Brain Metastases.
Authors: Mathew A , Mathew IE , Rosenzweig MQ , Brufsky AM 
Published: June 2012

Abstract
Background
Metastatic breast cancer (MBC) patients with brain metastases (BM) have a poorer prognosis compared to patients with metastases to sites such as bone or other visceral organs. The role of breast cancer subtypes such as triple negative (TN) status and its relationship with other known prognostic factors have not been well delineated in the context of metastatic disease to the brain. We conducted a retrospective single institution cohort study of MBC patients with BM to evaluate the association between TN subtype and overall survival from the diagnosis of BM.
Methods: Baseline demographic and tumor specific data including ER, PR and HER2 status were collected on newly diagnosed MBC patients between January 1998 and December 2009. Overall survival was determined from the date of diagnosis of BM. Survival analyses were performed using the Kaplan-Meier method and Cox proportional-hazards model.
Results: Data were available on 186 MBC patients with BM, of whom 156 died during a median follow-up of 10.2 months from the diagnosis of BM; median age was 47.9 years. 91% of patients were Caucasian; 25.3% had triple negative disease. Median survival from the period of diagnosis of BM in patients with triple negative disease was 7 months (Interquartile range, IQR: 3–13) as compared to 11 months (IQR: 5–22) in patients who were HER2−positive or ER/PR-positive. Multivariate analysis found a higher risk of death after BM for TN disease subtype, with a hazard ratio for death of 2.89 (95% confidence interval: 1.89−4.44; p&lt;0.001), when adjusted for variables such as age and stage at initial diagnosis of breast cancer, race, the number of metastatic sites, and the use of metastatic chemotherapy. The administration of metastatic chemotherapy had a significant survival benefit in the analyses, with a hazard ratio for death of 0.52 (95% CI: 0.27−0.99; p=0.048).
Conclusion: This retrospective cohort study in MBC patients with BM provides evidence for a greater risk of death in those with TN disease as compared to HER2−positive or ER/PR-positive subtypes even after adjusting for other prognostic factors.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-06.
P4-17-07: The Shifting Landscape of Metastatic Breast Cancer to the CNS.
Authors: Quigley MR , Fukui O , Chew B , Bhatia S , Karlovits S 
Published: June 2012

Abstract
Introduction: Improved survival following the diagnosis of breast cancer, in conjunction with new therapies and diagnostics has potentially altered the characteristics and course of patients presenting with CNS involvement.
Methods: Review of clinical and radiographic records of women presenting to a tertiary medical center with the new diagnosis of CNS metastatic disease from breast cancer. This was a retrospective review from patients identities obtained from two prospective databases Results: There were 88 women analyzed who were treated over the period 1/2003-2/2010, average age 56.9. At the time of initial presentation of CNS disease, 68% of patients had multiple brain metastases, 17% had a solitary metastasis and 15% had only leptomeningeal disease (LMD). The median survival for all patients from the time of diagnosis of breast disease was 50.0 months, and 9.7 months from diagnosis of CNS involvement. The only factor related to overall survival was estrogen receptor positive (ER+) pathology (57.6 v. 38.2 months, p=.02 log-rank); those related to survival post CNS diagnosis were presentation with LMD (p=.004, HR= 3.1, Cox regression) and triple negative hormonal/HER2 status (p=.02, HR= 2.3, Cox regression). Patients with either had a median survival of 3.1 months (no patients in common). Of the 75 patients who initially presented with metastatic brain lesions, 20 (26%) subsequently developed LMD in the course of their disease (median 10.4 months), following which survival was grim (1.8 months median). Of note was that HER2+ status was protective in regard to late development of LMD (14.7 vs. 42.3%, p=.03, Chi-square). Symptoms of LMD were most commonly lower extremity weakness (14/33), followed by cranial nerve deficits (11/33).
Conclusion: Treatment of patients with metastatic brain disease from breast cancer should be tailored to the patient's hormonal status (as it markedly effects survival) and practitioners must be vigilant for the development of LMD, especially as it often presents with non-descript complaints such as back pain.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-07.
P4-19-02: A Population-Based Study of Contemporary Systemic Therapy for Male Breast Cancer.
Authors: Bradley KL , Villa D , Speers CH , Woods R , Tyldesley S 
Published: June 2012

Abstract
Purpose: To describe the contemporary utilization, effectiveness and tolerability of tamoxifen, aromatase inhibitors, and trastuzumab in the treatment of early and advanced male breast cancer at a population level in British Columbia.
Patients and Methods: Records of 158 consecutive referred cases of invasive male breast cancer diagnosed from January 2000 to March 2010 were analyzed in a population-based cancer program with respect to patient and tumour characteristics, usage of endocrine agents, toxicity and medication adherence, trastuzumab usage and outcome. This group was compared to a population-based random sample of 1000 contemporary female breast cancer patients for prognostic and demographic factors. Survival outcomes were also compared to a cohort of women, matched 2:1 on prognostic and treatment factors.
Results: Pathology was most commonly infiltrating ductal carcinoma (94.3%) and estrogen-receptor positive (98.7%). Males were older (median 69.5 years) compared to women (median 60 years). Stage distribution was I (25.3%), II (43.0%), III (24.7%) and IV (7.0%), reflecting more advanced presentation compared to female cases I (43.9%), II (37.9%), III (12.5%) and IV (5.3%). Tamoxifen was prescribed as adjuvant therapy to109 patients, and as palliative therapy to 11. Fourteen (11.7%) patients discontinued tamoxifen due to toxicity. Aromatase inhibitors were prescribed as adjuvant therapy for 16 patients and as palliative therapy for 24; these were discontinued due to toxicity in 5 patients (12.5%). Five of 9 patients known to over-express Her2 were treated with adjuvant chemotherapy with trastuzumab. Overall survival, breast cancer-specific survival and progression-free survival at 5 years were 72.4%, 85.5% and 79.7%, respectively. There was no statistical difference in outcomes compared to the matched female cases.
Conclusions: In this large population-based study of contemporary systemic therapy for male breast cancer, outcomes appear to be similar to those of women with the same diagnosis. Side effect profiles, tolerance, adherence and outcomes after tamoxifen, aromatase inhibitors and trastuzumab appear to be similar in men compared to that described in the literature for women.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-19-02.
P5-01-02: Wnt5a Is a Prognostic Biomarker in Estrogen Receptor-Positive Premenopausal Breast Cancer.
Authors: Sand-Dejmek JT , Ehrnstrom R , Andersson T , Ryden L 
Published: June 2012

Abstract
Background
Wnt proteins belong to a family of secreted growth factors, which are involved in a wide range of cellular processes. Wnt signaling can be broadly divided into two categories; the canonical, β-catenin-dependent pathway and the non-canonical β-catenin-independent pathway. Wnt5a is a non-canonical signaling member of the Wnt family. Studies in two smaller cohorts of breast cancer revealed that loss of Wnt5a was associated with early relapse, metastatic disease and poor survival. Moreover, reconstitution of Wnt5a signalling decreased the migratory capacity and invasiveness of cultured breast cancer cells and administration of a Wnt5a-mimicking peptide was proven to inhibit metastases in a mouse model.
Material and methods: Premenopausal women (n=564) were included in a controlled randomised trial and allocated to tamoxifen for two years versus no adjuvant treatment. A tumour tissue microarrays was constructed and 390/500 samples were evaluable for Wnt5a protein expression by immunohistochemistry. Only cases with at least 2 evaluable cores were included. Wnt5a levels were determined semiquantitatively (scores 0–3). Clinical and pathological data such as patient age, histological subtype, pT stage, tumor size, pN stage, ER, PR, Ki67 and HER2 status were available. The end-point was 10 year recurrence-free survival.
Results: Wnt5a protein expression was lost in 158/390 of the analyzed tumors and more common in younger (&lt;45 yrs) women (p=0.032). Furthermore, loss of Wnt5a was significantly associated with ER and PR negativity (p=0.019 and p= 0.033, respectively). Loss of Wnt5a was significantly correlated to poor survival in the whole cohort, p=0.02. When analyzing the data according to breast cancer subtype, we found that Wnt5a was a strong independent prognostic factor in ER+ breast cancer p=0.009, but not in ER- breast cancer p=0.8. This was true both in the adjuvantely treated and untreated cohorts, verifying that Wnt5a indeed is a true prognostic factor and not a predictor of response to therapy.
Discussion: While associated with a better short-time prognosis than ER negative tumors, a subset of ER positive breast cancer patients are known to experience tumor recurrencies &gt;5 years after primary treatment and hence have a dismal prognosis. Those patients need to be identified and their tumors targeted with more aggressive treatment regimens. We have identified and validated Wnt5a as a prognostic biomarker in ER positive breast cancer in premenopausal women. Wnt5a signalling could potentially be reconstituted by administration of a Wnt5a-mimicking peptide, shown to inhibit metastases in mice, thereby offering ER positive premenopausal patients a targeted adjuvant therapy that potentially could lower their risk of metastatic disease.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-02.
P5-01-12: Identification of an ATM Activation Subtype in PTEN Mutant Breast Tumours.
Authors: McCabe N , Walker SM , Goffard N , Wikstrom K , Greenan C , Delaney T , McCarthy M , McDyer F , Hill L , Deharo S , Proutski V , Keating K , Mullan P , Harkin DP , Kennedy RD 
Published: June 2012

Abstract
Background PTEN is frequently lost in cancer cells through genetic mutation or epigenetic silencing. Loss of PTEN function has been widely reported to cause up-regulation of the PI3K/AKT signalling pathway resulting in increased cell growth, proliferation and survival. More recently it has been reported that PTEN null cells demonstrate genomic instability through increased ROS and oxidative stress induced DNA damage. The aim of this study was to identify a biomarker for PTEN status in human breast cancers.
Materials and Methods A metagene representing ATM activation was generated from public cell line data of AT fibroblasts treated with gamma-irradiation. This was used to perform hierarchical clustering analysis of a public DNA microarray profiling dataset with known PTEN IHC status. The metagene was validated in PTEN wildtype and null breast cancer cell lines.
Results We found that PTEN null cells have elevated levels of ROS and furthermore activation of the DNA damage signalling kinase, ATM. In agreement with this, the ATM metagene signature correlated with PTEN mutation in breast cancer tumours. Scoring of PTEN wildtype and null breast cancer cell lines using the metagene correlated with ATM activation and sensitivity to inhibition of ATM. Furthermore we show that inhibition of ATM caused DNA damage, cell cycle arrest and apoptosis in PTEN deficient cells suggesting a novel therapeutic strategy.
Conclusion These observations suggest that ATM may represent a therapeutic target in PTEN deficient tumours and furthermore ATM activation may also be an important biomarker of PTEN mutation or loss in breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-12.
P5-06-04: Mechanisms of Acquired Resistance to Insulin-Like Growth Factor 1 Receptor Inhibitor in MCF-7 Breast Cancer Cell Line.
Authors: Ekyalongo RC , Mukohara T , Kataoka Y , Kiyota N , Fujiwara Y , Minami H 
Published: June 2012

Abstract
Background: No studies have yet clarified the mechanism of acquired resistance to insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor (TKI). Our previous study of 16 breast cancer cell lines found that only MCF-7 expressed high levels of insulin receptor substrate (IRS)-1 and was sensitive to the IGF-1R-TKI NVP-AEW541.
Material and Methods: We developed a model of acquired resistance to NVP-AEW541 by continuously exposing MCF-7 cells to NVP-AEW541, naming the model MCF-7-NR. To explore the mechanism of acquired resistance to NVP-AEW541, the effects of NVP-AEW541 on cell growth and IGF-1R signaling in MCF-7 and MCF-7-NR cells were examined.
Results: With Western blot analysis, we found that MCF-7-NR had much lower levels of IRS-1 than parental MCF-7. While phosphorylation of Akt was completely inhibited by administration of NVP-AEW541 (3 μM) in both cell lines, phosphorylation of S6K remained high only in MCF-7-NR. The notion of Akt-independent S6K phosphorylation in MCF-7-NR was further supported by the fact that cell growth and phosphorylation of S6K was affected by administration of the Akt inhibitor perifosine to a lesser degree in MCF-7-NR than in MCF-7. Further, the mTOR inhibitor everolimus inhibited phosphorylation of S6K and cell growth equally in both lines. Screening of MCF-7 and MCF-7-NR lines for phosphorylation of 42 receptor tyrosine kinases with and without 3μM NVP-AEW541 showed that Tyro3 phosphorylation remained high only in MCF-7-NR cells. Gene silencing of Tyro3 using siRNA resulted in reduced cell growth, decreased phosphorylation of phosphoinositide-dependent kinase-1 (PDK-1) and protein kinase C α/βII, reduced expression of cyclin D1 in the MCF-7-NR line, with minimal effects evident in the MCF-7 line.
Discussion: Findings from our current study support the possibility of predicting sensitivity to NVP-AEW541 by measuring IRS-1 expression, as hypothesized in our previous study. Akt-independent activation of mTOR/S6K by an as-yet-undefined mechanism appears to induce acquired resistance to NVP-AEW541, and as such mTOR inhibitors may have therapeutic value. Tyro3 upregulation and migration of control of cellular growth and cyclin D1 expression may also induce resistance to NVP-AEW541. Although the validity of these findings should be evaluated in further preclinical studies and eventually in clinical trials, our observations may lead to individualized use of NVP-AEW541 and the development of “backup drugs” against tumors that acquire resistance to NVP-AEW541.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-06-04.
P5-06-11: Quercetin-3-Methyl Ether Inhibits Lapatinib-Sensitive and Lapatinib-Resistant Breast Cancer Cell Growth by Inducing G2/M Arrest and Apoptosis.
Authors: Bode AM , Li J , Zhu F , Normanno NE , Ericson ME , Lubet RA 
Published: June 2012

Abstract
Background: Lapatinib, an oral, small-molecule, reversible inhibitor of both EGFR and HER2, is highly active in HER2 positive breast cancer as a single agent and in combination with other therapeutics. However, resistance against lapatinib is an unresolved problem in clinical oncology. Recently, interest in the use of natural compounds to prevent or treat cancers has gained increasing interest because of presumed low toxicity. Quercetin-3-methyl ether, a naturally occurring compound present in various plants, has potent anticancer activity.
Material and Methods: Quercetin-3-methyl ether was obtained from Analyticon Discovery (Potsdam, Germany). Lapatinib-resistant SK-Br-3 (SK-Br-3-Lap R) cells were isolated in the laboratory of Cell Biology and Biotherapy at the Istituto Nazionale dei Tumori, Naples, Italy. Parental SK-Br-3 and SK-Br-3-Lap R cells were cultured in monolayers at 37 °C in a 5% CO2 incubator in 10% FBS/McCoy supplemented with penicillin/streptomycin (100 units/ml; Invitrogen). SK-Br-3 Lap R cells were routinely maintained in 1 μM lapatinib. Anchorage-dependent and -independent growth and cell cycle were assessed in the presence and absence of quercetin-3-methyl ether. Results: Here, we found that quercetin-3-methyl ether caused in a significant growth inhibition of lapatinib-sensitive and -resistant breast cancer cells. Western blot data showed that quercetin-3-methyl ether had no effect on Akt or MAPKs signaling in resistant cells. However, quercetin-3-methyl ether caused a pronounced G2/M block mainly through the Chk1-Cdc25c-cyclin B1/Cdk1 pathway in lapatinib-sensitive and -resistant cells. In contrast, lapatinib produced an accumulation of cells in the G1 phase mediated through cyclin D1, but only in lapatinib-sensitive cells. Moreover, quercetin-3-methyl ether induced significant apoptosis, accompanied with an increase the levels of in cleaved caspase 3, caspase 7 and poly(ADP-ribose) polymerase (PARP) in both cell lines.
Conclusion: Overall, these results suggested that quercetin-3-methyl ether might be a novel and promising therapeutic agent in lapatinib-sensitive or -resistant breast cancer patients.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-06-11.
P5-07-02: Could the Combination of COX-2 Inhibitor and Calcitriol Be a New Chemopreventive Approach To Decrease the Incidence of Breast Cancer?
Authors: Thill M , Cordes T , Fischer D , Hoellen F , Friedrich M , Diedrich K , Dittmer C 
Published: June 2012

Abstract
Background
COX-2 is a potential molecular prognostic factor for breast cancer and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is described as a tumour suppressor in cancer. The antiproliferative effects of calcitriol (1,25(OH)2D3) mediated via the vitamin D receptor (VDR) render vitamin D a promising target in breast cancer therapy.
Material and Methods: The expression of the prostaglandin (PG) metabolising enzymes (COX-2, 15-PGDH), the PG receptors, the vitamin D metabolising enzymes (1-alpha-hydroxylase, 24-hydroxylase) and the VDR were determined in benign and malignant breast cell lines as well as in normal and malignant breast tissue. Measurement of PGE2 and 25(OH)2D3 serum level in healthy women and breast cancer patients was performed in winter and summertime. Additionally, the influence of calcitriol on cell proliferation was determined. In addition we examined the effect of calcitriol on the enzyme expression.
Results: We found an inverse correlation between the expression of the PG metabolising enzymes with the VDR as well as with the vitamin D metabolising enzymes by investigating the tissue samples. Moreover, we detected an inverse correlation between the PGE2 and 25(OH)2D3 serum level in breast cancer patients during wintertime. Furthermore the PG receptors were associated with an increased carcinogenesis. The breast cell experiments presented a dysregulated vitamin D metabolism, especially in the invasive breast cell line. Calcitriol showed an antiproliferative effect only in the benign but not in the malignant cell lines, and the expression of COX-2 and 15-hydroxyprostaglandindehydrogenase was influenced by calcitriol only in the benign breast cell line.
Conclusions: These results suggest a link between vitamin D and PG metabolism and therefore a possible synergism between COX-2 inhibition and calcitriol in breast cancer cells. For the first time, we could show an inverse correlation between the two metabolisms in breast cancer on different levels. Thus, the chemopreventive combination of calcitriol and/or vitamin D analogue with a COX-2 inhibitor might decrease the incidence of breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-07-02.
P5-07-07: Follistatin Suppresses In Vitro Growth of Breast Cancer Cells and Its Reduced Expression in Breast Cancer Associated with Poor Differentiation and Prognosis.
Authors: Ye L , Mansel RE , Jiang WG 
Published: June 2012

Abstract
Background: Bone morphogenetic protein (BMP) belongs to TGF-β superfamily, being widely involved in prenatal and postnatal development and homeostasis of various tissues and organs. BMP signaling has been implicated in tumorigenesis and disease progression of certain malignancies. Recent studies demonstrated a profound role played Noggin, a BMP antagonist in bone metastasis from breast cancer. Current study examined expression of Follistatin, another BMP antagonist in a breast cancer cohort, and its relevance to pathological and clinical parameters.
Methods: Expression of Follistatin was examined in breast cancer tissues (n=93) and normal background tissues (n=30) using quantitative real time PCR and immunhistochemistry (IHC). The breast tissue samples were collected immediately after surgery. The clinical follow-up was routinely performed after surgery. The median follow-up period was 120 months (June 2004). Full-length human Follistatin coding sequence was cloned into a plasmid vector. Following transfection and verification, effect of Follistatin overexpression on cell growth was examined using an in vitro growth assay.
Results: IHC revealed cytoplamic staining of Follistatin in mammary epithelial cells in breast tissues. The staining appeared to be weaker in breast cancer, but there was no significant difference in its transcripts levels compared with that of normal background tissues. Follistatin transcripts were decreased in both moderately differentiated and poorly differentiated tumors, p=0.0165 and p=0.0169 in comparison with well differentiated tumors respectively. Transcript levels of Follistatin in primary tumors tended to be lower in the patients with poor prognosis (33.8±14.7) including those patients had local recurrence, metastases and died of breast cancer, p=0.09 when compared with that of patients remained disease free (117.0±46.0). Its expression appeared particularly lower in the patients died of the disease (21.8±12.0), p=0.05 v.s. disease free. Over-expression of Follistatin exerted inhibitory effect on in vitro growth of MDA-MB-231 cells.
Conclusions: Decreased expression of Follistatin in primary tumors of breast cancer correlates with poorer differentiation and mortality. Follistatin suppresses in vitro growth of breast cancer cells. It suggests that Follistatin is a negative regulator for tumor growth and disease progression of breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-07-07.