bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-12-04: Patterns of Trastuzumab-Based Treatment in Advanced Breast Cancer — Results from a Large GERMAN Non-Interventional Study
Authors: Jackisch C , Hinke A , Schoenegg W , Soeling U , Stauch M , Thomas G , Kuehn W , Gerhard K , Reichert D. 
Published: April 2011

Abstract
Background: In an ongoing, prospective observation study, treatment pattern of HER2 antibody-based treatment in metastatic breast cancer (MBC) in clinical routine is evaluated in Germany since 2001. Material and methods: A total of 1.687 patients (pts), presenting with Her2neu overexpressing MBC either pretreated (39%) or naïve to palliative chemotherapy (CT), were recorded in 202 German institutions. The median duration of fully documented therapy was 51 weeks. Additional information on trastuzumab (T) treatment beyond progression (TBP) was retrieved, as well as long-term outcomes, progression-free and overall survival (PFS, OS) in a subgroup of 940 pts, in which the treatment documentation had been finalized before July 2007.
Results: According to the most recent recommendations the majority of pts received T concurrently with chemotherapy (74%), 14% received T in combination with endocrine therapy (ETO). and 12% T as single agent therapy (SAT). In a multivariate logistic model, the choice of a non-cytotoxic regimen (ETO/SAT) was independently associated with the following pts characteristics: no visceral metastasis (p = 0.0000002), and positive hormone receptor status (p = 0.0018), while higher patient age (&gt; 65 y) (p = 0.061), and number of metastatic sites &lt; 2 showed a clear trend. No major correlation was observed between administration of cytotoxic treatment and relapse-free interval after initial diagnosis of breast cancer, adjuvant chemotherapy, adjuvant hormone therapy, and metastatic disease at initial diagnosis. After a median follow-up of more than 30 months (mo), median PFS (840 events) was 11.1, 9.9 and 19.1 mo and median OS (530 deaths) was 32.7, 39.6 and 48.8 mo in the CT, SAT and ETO group, respectively. Overall best response rates were 64%, 47%, and 45%.
Trastuzumab TBP was applied with a growing tendency over time and could be analyzed in a subgroup of 376 first-line patients with progression within approximately one year. The prolongation of trastuzumab remains to be strongly associated with longer survival after first progression in this updated analysis (medians: 15.1 vs. 20.6 mo; HR = 0.66, 95% CI: 0.49 - 0.88; p = 0.0045).
Conclusion: This large non-interventional trial reveals that 74% of all included patients were treated with trastuzumab plus CT which is considered standard of care for 1stline HER2+ MBC. The decision for not choosing a CT-based regimen was associated with good prognostic factors (no visceral metastasis, positive hormone receptor status, only one metastatic site) or higher age. Trastuzumab beyond progression is used increasingly in routine clinical practice and results in a prolonged survival.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-12-04.
Abstract P6-13-02: Survival Outcomes with Eribulin Mesylate vs. Treatment of the Physician's Choice (TPC) in Heavily Pretreated Subjects with Locally Recurrent or Metastatic Breast Cancer in North America, Western Europe, and Australia: Results of the Phase III EMBRACE Study
Authors: Vahdat LT , Twelves CJ , Seegobin S , Akerele C , Wanders J , Cortes J. 
Published: April 2011

Abstract
Background: Eribulin mesylate (E7389) is a nontaxane microtubule dynamics inhibitor. We conducted a randomized, controlled, open-label, phase III study to compare the efficacy and safety of eribulin vs. TPC in heavily pretreated subjects with locally recurrent or metastatic breast cancer. This report focuses on outcomes for participants enrolled in North America, Western Europe, and Australia (Region 1).
Methods: Eligible subjects had locally recurrent or metastatic breast cancer and had received 2-5 prior chemotherapy regimens, including an anthracycline and a taxane, with ≥2 of the regimens given for locally recurrent or metastatic disease. Subjects were stratified by geographic region, HER2/neu status, and prior capecitabine treatment. They were randomized 2:1 to receive eribulin 1.4 mg/m2 intravenously over 2-5 minutes on Days 1 and 8 every 21 days or an approved TPC. The primary endpoint was overall survival (OS); progression-free survival (PFS) was a secondary endpoint.
Results: A total of 762 subjects in 135 centers worldwide were enrolled. Subjects had a median age of 55 years, 92% were white, 76% were postmenopausal, and 81% had taxane-refractory disease. The median time since original diagnosis was 6.7 years. The majority of subjects (488 [64%]) were from Region 1, of whom 325 received eribulin and 163 received TPC. The most common treatments received by subjects from Region 1 in the TPC arm were vinorelbine (28%), gemcitabine (17%), capecitabine (13%), taxanes (20%), and anthracyclines (12%). 9% of subjects in this region received other therapies. Among the intent-to-treat population in Region 1, median OS was significantly prolonged with eribulin (13.3 months) vs. TPC (10.2 months) (HR: 0.724; 95% CI: 0.568-0.924; p=0.009). Median PFS was also prolonged with eribulin (3.3 months) vs. TPC (2.2 months; HR: 0.843; 95% CI: 0.666-1.066; p=0.153) in this population, as assessed by independent reviewers.
Conclusion: OS was significantly prolonged in eribulin-treated patients participating in the EMBRACE trial in the North America, Western Europe, and Australia region. When assessed by independent review, PFS was also prolonged with eribulin, although this difference did not reach statistical significance for this geographic region.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-02.
Abstract P6-13-03: Local Treatment Strategies in Young and Elderly Stage IV Breast Cancer Patients in the USA and The Netherlands
Authors: van de Water W , Bastiaannet E , van de Velde S , Dekkers OM , Margenthaler JA , Deshpande AD , Jeffe DB , de Craen AJM , van de Velde CJH , Liefers GJ. 
Published: April 2011

Abstract
Introduction
Approximately 5-10% of breast cancer patients present with stage IV at diagnosis. The appropriate treatment is still under debate. This study focused on differences in treatment regimens between the United States (USA) and the Netherlands (NL) within age groups.
Methods
As we included data from NL and the USA, we were able to construct an instrumental variable as a substitute for randomization and get around selection bias. We compared Dutch and USA treatment strategies; restrictive versus more often extensive local therapy. Data from the NL Cancer Registry and the US Survaillance, Epidemiology and End Results Program were used to construct a database for analyses. All primary stage IV breast cancer patients diagnosed in 1995-2003 were included. Follow up cutoff date was 12- 31-2005 (USA) and 12-31-2008 (NL). Analyses were stratified by age (&lt;65, 65-75 and ≥75 years). Chi Square Tests were performed for therapy rates, overall survival was calculated by Cox Proportional Hazard Analyses.
Results
A total number of 11030 patients were included (5354 NL, 5676 USA). Within each age category, surgery was applied more often in the USA (&lt;65: NL37%-USA52%, P&lt;0.001. 65-75: NL28%-USA42%, P&lt;0.001. ≥75: NL21%-USA39%, P&lt;0.001).
Similar results were observed for use of radiotherapy after surgery (&lt;65: NL30%-USA47%, P&lt;0.001. 65-75: NL26%-USA44%, P&lt;0.001. ≥75: NL 17%-USA36%, P&lt;0.001). Rate of radiotherapy without surgery did not differ between the two countries. With increasing age, use of surgery and use of radiotherapy after surgical treatment decreased (NL, USA each P&lt;0.001). Use of radiotherapy without surgical intervention however increased with age in both countries (NL p=0.002, USA p=0.001). Although unadjusted analysis showed enhanced overall survival for patients &lt;65 years of age in the USA compared to NL (HR 0.92 (0.86-0.98), p=0.006), these results were not confirmed in multivariable analyses. Patients ≥75 years of age in the USA compared to NL, however, had worse overall survival, confirmed in multivariable analyses (HR 1.17 (1.08-1.27), P&lt;0.001).
Conclusion
Surgery and radiotherapy after surgical treatment for stage IV breast cancer patients was applied more often in the USA compared to NL in all age categories. Use of local therapy decreased with increasing age. In multivariable analyses, patients ≥75 years of age had a worse overall survival in the USA. This finding suggests that a more extensive local treatment strategy does not improve overall survival in this group of elderly patients. The opposite was true for young patients, although these results were not confirmed in multivariable analyses.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-03.
Abstract P6-14-01: Effect of Denosumab Versus Zoledronic Acid Treatment in Patients with Breast Cancer and Bone Metastases: Results from the Extended Blinded Treatment Phase
Authors: Stopeck A , Martin M , Ritchie D , Body J-J , Paterson A , Viniegra M , Jassem J , Takano T , Van Poznak C , Bourgeois H , Fan M , Dansey R , Braun A. 
Published: April 2011

Abstract
Background: Denosumab is a fully human monoclonal antibody which inhibits RANKL, a key mediator of osteoclast activity. Results from the primary analysis of this pivotal phase 3 trial showed that denosumab was superior to zoledronic acid (ZA) in delaying the time to first on-study skeletal-related events (SRE) in patients with breast cancer and bone metastases. We now report results including an additional 4 months of blinded treatment.
Methods: Randomized patients received either subcutaneous (SC) denosumab (120 mg) and intravenous (IV) placebo or IV ZA (4 mg, adjusted for renal function) and SC placebo every 4 weeks. No dose adjustments were made for SC denosumab. All patients were advised to take daily calcium (≥500 mg) and vitamin D (≥400 IU) supplements. The primary endpoint was time to first on-study SRE (predefined as pathologic fracture, radiation or surgery to bone, or spinal cord compression). Time to first and subsequent SRE (multiple event analysis) and safety endpoints were also evaluated. Analyses for the extended treatment phase are considered exploratory.
Results: Overall, 2046 patients enrolled: 1026 were randomized to denosumab and 1020 were randomized to ZA. Denosumab was superior to ZA in delaying the time to first on-study SRE by 18%, and the time to first and subsequent on-study SRE by 22% (Table). The median time to first on-study SRE was 5 months longer for the denosumab group (32.4 months) than the ZA group (27.4 months). Overall survival and disease progression were similar for both treatment groups. Similar percentages of subjects reported adverse events (AEs; 96.2% denosumab, 97.4% ZA) and serious AEs (47.9% denosumab, 50.2% ZA). Positively adjudicated cases of osteonecrosis of the jaw were reported in 2.5% (n=26) of denosumab-treated patients and 1.8% (n=18) of ZA-treated patients (P=0.29). Hypocalcemia was reported by 62 (6.1 %) patients in the denosumab group and 37 (3.7%) patients in the ZA group.
Conclusion: Among patients with breast cancer and bone metastases, denosumab was superior to ZA in delaying or preventing SREs, and continued treatment with denosumab resulted in a median time to first SRE that was 5 months longer than treatment with ZA. Denosumab, with its novel mode of action, may represent a potential treatment option for patients with breast cancer and bone metastases without the need for dose adjustment or renal monitoring.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-01.
Abstract P6-14-05: Final Overall Survival Analysis of the TBP Phase III Study (GBG 26/BIG 3-05): Capecitabine vs. Capecitabine + Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing during Trastuzumab Treatment
Authors: von Minckwitz G , Schwedler K , Schmidt M , Barinoff J , Mundhenke C , Cufer T , Maartense E , de Jongh F , Baumann K , Bischoff J , Harbeck N , Lück H-J , Maass N , Zielinski C , Andersson M , Stein R , Nekljudova V , Loibl S. 
Published: April 2011

Abstract
Background: In women with HER2-positive breast cancer progressing during trastuzumab treatment, continuation of trastuzumab plus capecitabine (XH) showed a significantly improved overall response rate and time to progression compared with capecitabine (X) alone (von Minckwitz et al, J Clin Oncol 27:1999-2006, 2009). Here we report the final analysis of overall survival (OS).
Methods: Patients (pts) with HER2-positive, locally advanced or metastatic breast cancer who progressed during treatment with trastuzumab with or without adjuvant and/or 1st-line metastatic chemotherapy were prospectively randomized to X (2500 mg/m2 on days 1-14, q3w) or XH (6 mg/kg, q3w). OS was a pre-specified secondary endpoint of the study. Results: Median follow up at June 2010 was 20.7 months. 59 of 74 and 60 of 77 pts died in the X alone and XH arm, respectively. Median OS was 20.6 and 24.9 months with X alone and XH, respectively. This difference was not statistically significant (HR=0.94 [0.65-1.35]; p=0.73). Cox proportional hazard model showed performance status, hormone receptor status and metastatic site as independent prognosticators for survival. No difference between treatment arms was observed for pts with a clinical response or clinical benefit, respectively. Pts who continued/restarted anti-HER2 treatment (trastuzumab or lapatinib) after 2nd progression (N=88) had an OS of 18.8 compared with 13.3 months for those who did not receive 3rd line treatment with anti-HER2 agents (N=52) (HR 0.63; p=0.02). Pts who continued treatment after progression as initially randomized (anti-HER2 treatment after XH (N=31) or no anti-HER2 treatment after X alone (N=53)) had an OS of 26.7 months and 20.4 months (HR 0.71; p=0.2). Conclusions: Final OS analysis of the GBG-26 study could not demonstrate a survival benefit for treatment beyond progression with trastuzumab. However in a post-hoc analysis, pts receiving anti-HER2 treatment as 3rd line therapy showed a better OS than those not receiving this targeted treatment.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-05.
Abstract P6-14-14: Concerted Anti-Tumor/Radiosentizing Effect of Epigallocatechin Gallate, Resveratrol and Genistein by Targeting Tumor Invasion and Metastasis Molecules in Human Breast Cancer Cells
Authors: Veeraraghavan J , Kardokus K , Natarajan M , Aravindan S , Herman TS , Aravindan N. 
Published: April 2011

Abstract
Accomplishing the desired anti-tumor efficacy with individual dietary phytochemicals is clinically unachievable. This is due to the existence of converging and diverging pathways spanning the complex metabolic networks in cancer cells. This complexity demands the development of a multi-component approach with physiological doses of phytochemicals that could be used as “deliverable” anti-cancer agent. To address this concern, we investigated the synergistic efficacy of Genistein (GEN), Epigallocatechin gallate (EGCG) and Resveratrol (RES) in mitigating cancer progression. Human breast adenocarcinoma cells (MCF-7 and MDA-MB-231) were treated with physiological concentration of GEN, EGCG, RES, individually or all three together (GER). In parallel cultures cells were treated with GER and either exposed to radiation (2Gy;IR) or treated with β-estradiol (≥2E, positive control). The trated cells were examined after 24h. In MCF-7 cells, QPCR profiling of 93 tumor invasion and metastasis molecules revealed that EGCG, RES and GEN significantly (≥2 fold) induced 23, 36, 22 genes and completely suppressed 61, 40 and 64 genes respectively as stand-alone compounds. Conversely, GER completely knocked down the transcription of 82 genes, while another 9 genes were maintained at baseline level. More importantly, GER significantly inhibited 75 and 63 genes in ≥2E and IR exposed MCF-7 cells. Interestingly, in highly metastatic MDA-MB-231 cells, EGCG, RES, GEN significantly induced 17, 19, 2 genes and completely suppressed 41, 26 and 57 genes respectively as stand-alone compounds. Conversely, GER completely suppressed 67 genes while another 17 genes were maintained at baseline level. To that end, GER significantly inhibited 57 and 59 genes and maintained 16 genes at basal level in ≥2E and IR exposed MCF-7 cells. Taken together, these data evidently exhibit the potential synergestic effect of EGCG, GEN and RES in mitigating breast cancer progression as opposed to their stand alone effect. More importantly, these data strongly suggests that GER potentiates synergistic radiosensitization in these cells and this GER influenced radiosensitization may involve selective targeting of tumor invasion and metastatic transcription.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-14.
Abstract P6-14-17: In Vitro Evaluation of the Anti-EGFR Antibody Cetuximab and the Anti-HER2 Antibody Trastuzumab in a Panel of Human Tumor Cell Lines
Authors: Marcoe KF , Ovechkina Y , Keyser R , Bernards K , Chestnut-Speelman J , Yoshino K , O'Day C. 
Published: April 2011

Abstract
The epidermal growth factor receptors, EGFR (erbB-1) and HER2 (erbB-2), and their down stream signaling events promote tumor growth and survival in a variety of epithelial tumors. Current treatment strategies used to target these receptors include mAbs directed against their extracellular domains and small molecule inhibitors of their tyrosine kinase activities. The efficacy of these types of therapeutics is increasingly being found to be contingent on the genotype of the targeted cancer. In vitro evaluation of mAbs is reliant on selection of tumor cell lines driven by the specific antigen proteins of interest and their associated pathways. We selected a panel of eight human tumor cell lines, six breast cancer (BT474, SK-BR-3, MDA-MB-453, MDA-MB-231, MDA-MB-468 and MCF-7), one colon (SW48) and one skin (A431) with varying levels of HER2, EGFR and EGFR/HER2 expression to evaluate the mAbs cetuximab and trastuzumab for antiproliferative effects, ability to induce apoptosis and the ability to block cell cycle. These findings were compared to results obtained after treatment with lapatinib, erlotinib, Ly294002 and Tamoxifen. The BT474 and SK-BR-3 breast cancer cell lines with HER2 amplified expression demonstrated cytostatic antiproliferative and G1/S cell cycle block sensitivity to the anti-HER2 antibody trastuzumab. The more prominent inhibitory effects observed in the BT474 cell line were further confirmed by measurable induced decreased levels of phospho-Akt and increased levels of the CDK2 inhibitor p27Kip1 following treatment with trastuzumab, lapatinib and Ly294002. The SW48 colon and A431 skin cancer cell lines with EGFR mutations and EGFR over expression, respectively, demonstrated cytostatic antiproliferative sensitivity to the anti-EGFR antibody cetuximab. This in vitro cell-based multiplexed approach for assessment of oncology therapeutics based on genetically directed cell line selection, demarcation of cytostatic and cytotoxic cell proliferation inhibition and assessment of receptor down stream signaling biomarkers offers greater predictive efficacious value and can be used to identify optimal candidates for combination therapies.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-17.
Abstract P6-15-03: Phase Ib Trial of the Gamma Secretase Inhibitor (GSI), MK-0752 Followed by Docetaxel in Locally Advanced or Metastatic Breast Cancer
Authors: Schott AF , Chang JC , Krop IE , Griffith KA , Layman RM , Hayes DF , Wicha MS. 
Published: April 2011

Abstract
Background: The cancer stem cell hypothesis asserts that there is a small population of cells within a tumor that has the ability to self renew and differentiate, and that these cells drive tumor growth and metastasis but are resistant to conventional cytotoxic chemotherapy. Pathways involved in stem cell growth and differentiation are viable targets for new anticancer therapies. One such pathway, Notch, is inhibited by GSIs which prevent translocation of Notch intracellular domain to the nucleus. Inhibition of GS concurrent with chemotherapy might improve disease control by targeting both stem cells and differentiated cells within the tumor. This Phase Ib clinical trial was designed to determine the MTD of the GSI, MK-0752, in combination with docetaxel, and to evaluate an effect on stem cell markers in serial tumor biopsies.
Methods: Eligible subjects had metastatic breast cancer or locally advanced breast cancer that did not respond to anthracycline therapy. Patients with disease that progressed on a taxane, or who had received a taxane within 6 months were excluded. MK-0752 was administered orally on days 1-3 of each 21-day cycle of therapy, in escalating doses. Dose levels (mg/day) 1=300; 2=450; 3=600; and 4=800. Docetaxel 80 mg/m2 IV was administered day 8, with pegfilgrastim day 9 each cycle. Treatment was continued until disease progression, unacceptable toxicity, or symptomatic deterioration. The trial was monitored using the Time to Event Continual Reassessment Method, targeting a 20% toxicity rate. Tumor biopsies were performed at baseline, after 1 cycle, and at treatment completion in a subset of patients.
Results: 30 patients were enrolled between Mar 2008 and Jan 2010. Dose limiting toxicities of the combination included diarrhea, hand-foot syndrome, and LFT elevation. 20/30 patients experienced Grade 1 or 2
fatigue. The final estimates and confidence intervals for the probability of dose limiting toxicity at each dose level are summarized in the table:
Probability = probability of dose-limiting toxicity 20 enrolled patients had measurable disease by RECIST criteria. Of these, 9 had PR, 8 SD, and 3 PD, for an estimated RR of 45% to the combination. 2 patients have been maintained on therapy in excess of 22 cycles. Conclusions: Dose level 3 was identified for further study in a Phase II randomized trial. Efficacy of docetaxel was not inhibited by MK-0752, as a 45% RR in patients with measurable disease was observed. There is intriguing long term disease stabilization in 2 patients. Evidence of an effect of the combination on the stem cell population was apparent on serial biopsies as presented at SABCS Dec 2009 (Abstract # 48); additional biopsy data will be presented.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-03.