bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-18-18: Lapatinib versus trastuzumab, or both, added to preoperative chemotherapy for breast cancer: A meta-analysis of randomized evidence
Authors: Valachis A , Nearchou A , Lind P 
Published: August 2014

Abstract
Purpose: We compared the efficacy and safety of the addition of lapatinib versus trastuzumab, or the combination, to neoadjuvant chemotherapy in HER2-positive breast cancer.
Methods: Potentially eligible trials were identified through PubMed and Cochrane Library searches and abstracts of major international conferences. The endpoints that we assessed were pathologic complete response (pCR) rate and toxicity. Pooled relative risks (RR) were estimated for each endpoint with fixed or random effects models, depending on between-studies heterogeneity.
Results: Six trials were identified with 1494 eligible patients. The probability to achieve pCR was higher for the trastuzumab plus chemotherapy arm than lapatinib plus chemotherapy (RR 1.25, 95% Confidence Interval (CI): 1.08–1.43; p-value = 0.003) (6 trials; 1494 patients). Furthermore, the probability for pCR was significantly higher in the group given both lapatinib and trastuzumab than in the group given trastuzumab alone (RR 1.39, 95% CI: 1.20–1.63; p-value &lt; 0.001) (4 trials; 779 patients). Diarrhea and dermatologic toxicities were statistically more frequent in patients receiving lapatinib than trastuzumab. The combination was associated with a higher rate of diarrhea than trastuzumab alone. No differences were observed regarding cardiac adverse events among patients receiving trastuzumab, lapatinib, or the combination.
Conclusion: These data support the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer in the neoadjuvant setting. The direct comparison of trastuzumab and lapatinib demonstrated that lapatinib is inferior in terms of pCR and toxicity.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-18.
Abstract P5-18-21: A Phase II randomized trial of lapatinib with either vinorelbine or capecitabine as first- and second-line therapy for ErbB2-overexpressing metastatic breast cancer (MBC)
Authors: Janni W , Sarosiek T , Pikiel J , Karaszewska B , Staroslawska E , Salat C , Caglevic C , Potemski P , Brain E , Briggs K , de Silvio M , Sapunar F , Papadimitriou C 
Published: August 2014

Abstract
Background: Lapatinib (L), a dual kinase inhibitor of epidermal growth factor receptor and ErbB2, is effective in the treatment of ErbB2+ MBC in combination with capecitabine (C) following progression after trastuzumab, anthracyclines, and taxanes. Vinorelbine (V) is an important chemotherapy option in MBC, and multiple Phase II trials have been conducted in combination with trastuzumab. This randomized, open-label, multicenter, Phase II study (LAP112620, VITAL) evaluated the efficacy and safety of L with either V or C in women with ErbB2+ MBC.
Methods: Patients with MBC who had received ≤1 chemotherapy regimen in the metastatic setting were randomized 2:1 to either L 1250 mg orally once daily (QD) continuously plus V 20 mg/m2 intravenously on Days 1 and 8, every third week, or L 1250 mg orally QD continuously plus C 2000 mg/m2/day orally in 2 doses 12 hours apart on Days 1–14 every third week. Patients were stratified by prior receipt of therapy for MBC (Y/N) and site of metastatic disease (visceral/soft tissue or bone-only). The primary endpoint of progression-free survival (PFS) was assessed once all subjects had been followed for a minimum of 6 months or had otherwise progressed, died or withdrawn, if sooner. The primary focus was to evaluate PFS in the L plus V arm with a descriptive intent only. Other endpoints included overall response rate, overall survival, and safety. Patients progressing on one treatment arm were given the option of crossing over to the other arm.
Results: 112 patients were randomized. The results and conclusions sections will be updated once the primary analysis has been completed in September 2012.
ClinicalTrials.gov - NCT01013740
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-21.
Abstract P5-18-23: The prognosis of T1a, T1b N0 M0, HER2+ patients in Korea.
Authors: Lee JW , Moon H-G , Han W , Noh D-Y 
Published: August 2014

Abstract
Backgrounds: Increased expression of HER-2 or amplification of the HER-2/neu gene has been associated with a worse prognosis than with other breast cancer phenotypes. Especially in cases of size of 0.5∼1cm and node-negative status, adjuvant chemotherapy with or without Trastuzumab treatment is suggested by recent National Comprehensive Cancer Network(NCCN) guidelines. In Korea, the breast cancer patient pool is more younger than western data, and there could be some ethnic differences.
Methods: The Korean Breast Cancer Society (KBCS) has been collaborating with the Korean Central Cancer Registry (KCCR) to improve the completeness and validity of the breast cancer registry and the mortality data. Data of T1a, bN0M0 breast cancer patients from 1999 to 2006 from KBCS on-line registry was obtained, and a total of 2,962 patients were included for survival analysis.
Results: 711 patients (24.0%) was HER-2 positive. Hormone receptor and HER2 status was used to classify 4 molecular subtypes; Hormone receptor(HR)+/HER2−, HR+/HER2+, HR−/HER2+, HR−/HER2−. The median follow-up was for 55.82 month (±24.196). Breast cancer specific survival rate was lowest at HR−/HER2+ subtype(97.9%). It's 1.0∼1.8% lower than other subtypes. Between all T1N0M0 cases, especially T1b HR−/HER2+ cases showed lowest survival of 96.4%.
Conclusion: This study calculated the nationwide survival rates of Korean breast cancer patients with T1a, bN0M0 disease for the first time. HER2 gene positivity was associated with worse prognosis and it's concordant with western studies. But prognosis of T1N0M0 lesion is much better than that of other nations. So, the usage of chemotherapy and Trastuzumab treatment should be considered more carefully in Korea. Further analysis of the long-term survival and a nationwide collaborative study should be performed to estimate the survival trend of Korean breast cancer patients.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-23.
Abstract P5-18-25: Bispecific Fynomer-antibody fusion proteins targeting two epitopes on HER2
Authors: Grabulovski D , Brack S , Toller I , Mourlane F , Bertschinger J 
Published: August 2014

Abstract
Background: Fynomers are small binding proteins (7 kDa) derived from the human SH3 domain of Fyn kinase. They can be engineered to yield specific and high-affinity binding domains to target proteins of interest. In the past, we have isolated Fynomers with excellent physico-chemical properties binding to 16 different antigens. One important application of the Fynomer technology represents the genetic fusion of a Fynomer to an antibody to provide bispecific fusion proteins with enhanced activity compared to the unmodified antibody.
Method: Using phage display technology we have isolated Fynomers binding to an epitope on HER2 which is different from the epitopes recognized by trastuzumab and pertuzumab. After genetic fusion of the HER2 binding Fynomers to pertuzumab the resulting bispecific fusion proteins were evaluated in vitro and in vivo for their antitumoral activity.
Results: The fusion of Fynomers to pertuzumab did not alter the favorable biophysical properties of pertuzumab: First, the Fynomer-antibody fusion proteins could be purified with the same high yields from the supernatant of transiently transfected CHO cells as the unmodified antibody pertuzumab (in the range of 100 mg/L). Second, the purified fusion proteins were monomeric and showed no signs of aggregation even after four months of storage at 4 °C or −20 °C in PBS as determined by size exclusion chromatography. Third, the fusion of Fynomers to antibodies did not alter their Fc-mediated effector functions. Antibody-dependent cellular cytotoxicity (ADCC) was maintained, and the affinity to the neonatal Fc-receptor (FcRn) was similar as observed for pertuzumab. In addition, the bispecific Fynomer-antibody fusion proteins demonstrated excellent growth inhibition of tumor cells in vitro compared to pertuzumab and trastuzumab. In particular, the most potent molecule COVA208 exhibited impressive efficacy in vivo in tumor xenograft mouse models.
Conclusion: These encouraging preclinical results indicate that the bispecific Fynomer-antibody fusions have highly promising properties with a great potential for further preclinical and clinical development, both alone and in combination with trastuzumab.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-25.
Abstract P5-19-01: Targeting the HER3-phosphatidyl inositol-3 kinase pathway in breast cancers
Authors: Cook RS , Morrison MM , Arteaga CL , Perou CM 
Published: August 2014

Abstract
Background: Using a mouse model of HER3 ablation in the mammary epithelium, we previously showed that HER3 is required for the genesis of transgenic HER2-overexpressing breast cancers. However, increasing evidence suggests that transgenic models of HER2 overexpression result in luminal B-like mammary tumors, which resemble human breast tumors that express estrogen receptor (ER) but are often not responsive to endocrine therapy. Furthermore, we found that HER3 is required in the untransformed mouse mammary epithelium for differentiation and survival of luminal cells, but not basal cells. Herein we report that HER3 drives growth and survival of luminal breast cancers in a manner that parallels its role in maintaining the untransformed luminal epithelium in the breast.
Results: Expression profiling of a large human breast cancer dataset demonstrated that HER3 expression was highest in Luminal breast cancers as compared to different molecular subtypes of breast cancers, including HER2-enriched, claudin-low, and basal-like breast cancers. In luminal breast cancer cell lines MCF7, ZR75-1, and MDA-MB-361, HER3 targeting using siRNA or a monoclonal antibody against HER3 decreased Akt, S6, and Erk1/2 phosphorylation, cell growth and cell survival under conditions of estrogen deprivation. Luminal breast tumor xenografts treated with U3-1287, a humanized monoclonal anti-ErbB3 antibody, or EZN-3920, an anti-sense oligonucleotide against ErbB3, decreased tumor growth and phosphatidyl inositol-3 kinase (PI3K)/mTOR signaling in vivo. Interestingly, luminal breast tumor xenografts responded to the ER inhibitor fulvestrant with increased HER3 expression and phosphorylation, and with increased PI3K/mTOR signaling as shown by enhanced S6 phosphorylation. Fulvestrant-mediated upregulation of HER3 was also seen in matched clinical breast tumor specimens harvested before treatment and after 21 days of fulvestrant treatment. AMG-888 blocked fulvestrant-induced HER3 and phospho-S6 upregulation in vivo, resulting in regression of luminal breast tumor xenografts.
Conclusions: These data suggest that HER3 targeting may improve the outcome of luminal breast cancers treated with endocrine therapy, and are consistent with our findings that a HER3-dependent expression signature positively correlates with relapse in tamoxifen-treated patients. Taken together, these results define a novel role for HER3 in luminal breast cancer cells, and support future investigations into therapeutic strategies to target HER3 in luminal breast cancers.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-19-01.
Abstract P5-19-02: Selective PI3K and dual PI3K/mTOR inhibitors enhance the efficacy of endocrine therapies in breast cancer models
Authors: Friedman L , Ross LB , Wallin J , Guan J , Prior WW , Wu E , Nannini M , Sampath D 
Published: August 2014

Abstract
Purpose: Phosphoinositide 3-kinases (PI3K) are lipid kinases that can regulate breast tumor cell growth, migration and survival. Standard of care drugs such as estrogen receptor (ER) antagonists including fulvestrant and tamoxifen, and aromatase inhibitors such as letrozole are indicated for the treatment of hormone receptor positive breast cancer. The current study is focused on investigating preclinical activity in breast cancer models, for GDC-0941, a class I PI3K inhibitor, GDC-0032, a PI3K inhibitor, and GDC-0980, a dual mTOR kinase and class I PI3K inhibitor. Investigation into PI3K inhibitor efficacy in combination with endocrine therapies is also explored.
Experimental Design: A panel of ER+ breast cancer cell lines were treated with GDC-0941, GDC-0032 and GDC-0980 either as single agents or in combination with fulvestrant or tamoxifen and assayed for cellular effects. MCF-7 cells ectopically expressing aromatase were utilized to test the efficacy of aromatase inhibitors in combination with PI3K inhibitors in vitro. In addition, human xenografts of breast cancer cell lines were employed to assess combination efficacy of PI3K inhibitors with fulvestrant and tamoxifen in vivo.
Results: Combination of GDC-0941, GDC-0032 or GDC-0980 with endocrine therapies resulted in a decrease in cellular viability and an increase in cell death. Synergy of PI3K inhibitor combinations with fulvestrant or tamoxifen was assessed using Combination Index (C.I.), and C.I. values as low as 0.1 indicated strong synergy in some contexts. Combination activity of PI3K inhibitors and letrozole was also observed in MCF7 cells expressing aromatase. In MCF-7 xenografts, the combination of GDC-0980, GDC-0032 and GDC-0941 enhanced activity of fulvestrant resulting in tumor regressions and tumor growth delay (116% tumor growth inhibition (TGI) for GDC-0980 and 91% TGI for GDC-0941 and GDC-0032). In addition, the combination of GDC-0941 or GDC-0032 with tamoxifen enhanced the efficacy of tamoxifen in vivo (83%TGI for GDC-0941 and 102%TGI for GDC-0032). Mechanism of action and biomarker studies are underway.
Conclusion: Collectively, the non-clinical efficacy data provide a strong rationale to evaluate the combination of PI3K inhibitors with anti-estrogen therapy in hormone receptor positive breast cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-19-02.
Abstract P5-20-11: Bevacizumab in metastatic breast cancer: a retrospective matched-pair analysis.
Authors: Gampenrieder SP , Romeder F , Muß C , Pircher M , Ressler S , Rinnerthaler G , Bartsch R , Sattlberger C , Mlineritsch B , Greil R 
Published: August 2014

Abstract
Background: In November 2011 the FDA withdrew accelerated approval of the breast cancer indication for bevacizumab, because “the drug has not been shown to be safe and effective for this use” (FDA Commissioner M. A. Hamburg, MD). The objective of this analysis was to evaluate efficacy and safety of bevacizumab in non-selected patients with stage IV breast cancer.
Patients and methods: All patients with metastatic breast cancer treated with bevacizumab in combination with chemotherapy in our institution between 2005 and 2011 were retrospectively analysed. At least 1 cycle of bevacizumab was required for safety analysis, 3 applications for efficacy evaluation. A control group was matched according to the following criteria: receptor status, line of treatment, chemotherapy backbone, visceral or non-visceral disease and age.
Results: A total of 213 patients fulfilled the inclusion criteria. All of them were evaluable for toxicity, 199 for response. 503 potential controls allowed a complete matching for 103 patients. Fifty-eight percent of patients received first-line, 15% second-line and 27% of patients beyond second-line treatment. Visceral metastases were present in 69% of patients in both groups. The most common chemotherapy backbones were paclitaxel, capecitabine and docetaxel with 44%, 32% and 19%, respectively.

Most common grade 3/4 toxicities related to bevacizumab were hypertension (27%), proteinuria (1%), thromboembolism (9%) and bleeding events (1%). Interestingly, patients developing hypertension during bevacizumab treatment had a more favourable outcome (PSF 11.7 vs. 5.7 months, p &lt; .001; OS 27.4 vs. 14.5 months, p &lt; .001). Since the median time until apparent blood pressure elevation was only 1.4 months, this provides a simple biologic biomarker for bevacizumab efficacy.
Conclusion: Bevacizumab in combination with chemotherapy appears to be an effective, well-tolerated regimen in the treatment of advanced breast cancer even in a non-selected, partly intensively pre-treated population. Bevacizumab induced hypertension predicted a better PFS and OS.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-11.
Abstract P5-21-04: Real-world use and effectiveness of adjuvant trastuzumab in 2665 consecutive breast cancer patients
Authors: Tjan-Heijnen VCG , Seferina SC , Lobbezoo DJA , Voogd AC , Dercksen MW , van den Berkmortel F , van Kampen RJW , van de Wouw AJ , Joore MA , Borm GF 
Published: August 2014

Abstract
Background The impact of drug prescriptions in the real world as opposed to strict trial prescription is only rarely assessed even though it is well recognized that incorrect use may harm a patient and may have a huge impact on health care resources. We aimed to assess how and to whom trastuzumab was given since its introduction in September 2005 as adjuvant treatment, and to assess its efficacy in daily practice.
Patient and methods We set up a registry of all patients diagnosed with stage I-III invasive breast cancer in 5 Dutch hospitals during the years 2005–2007. Patients were included irrespective of HER2 status and of treatment received. We present the main patient and tumor characteristics, treatment delivered and 5-year treatment outcomes.
Results Of 2665 patients included, n=479 (18%) had a HER2 positive tumor. As of September 2005, adjuvant trastuzumab was given to 96% of patients with a HER2 positive tumor receiving adjuvant chemotherapy. The median age of these patients was 51 (27–72) years. Their median tumor size was 23 (5–65) mm, 55% had node-positive, 57% ER-positive and 47% PR-positive disease. In 83% of patients, trastuzumab was delivered in sequence after (taxane-based) chemotherapy, mainly in the first years after introduction, and in 91% in a 3-weekly regimen. Trastuzumab was delivered for a median of 49 (IQR 45–52) weeks. For patients with a HER2 positive tumor treated with adjuvant trastuzumab (n = 232), the five-year disease-free survival was 81%. For patients with a HER2 positive tumor who were not treated with trastuzumab (n = 247) the five-year disease-free survival was 75% (p = 0.13). Corresponding 5-year overall survival rates were 91% and 78%, respectively (p = 0.0002).
Conclusion In the Netherlands, trastuzumab was rapidly implemented since its introduction in September 2005. Characteristics of patients treated with trastuzumab resembled those included in the HERA study. Similarly, outcomes were in agreement with reported phase III studies. More detailed and multivariate analyses will be shown at the meeting.
Funding Netherlands Organization for Health Research and Development (ZonMw: 80–82500-98-9056) and Roche Netherlands.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-21-04.
Abstract P6-01-03: Decreasing the metastatic potential in Triple Negative Breast Cancer through the miR-17 cluster
Authors: Jin L , Simone B , Sano Y , Lim M , Zhao S , Savage JE , Baserga R , Camphausen K , Simone NL 
Published: August 2014

Abstract
Background: In animal models of breast cancer, caloric restriction (CR), or a 25–30% reduction of calories, has decreased tumor initiation and progression. We sought to determine if CR could be used as a novel therapeutic intervention to enhance cytotoxic therapies such as radiation (RT) and alter the molecular profile of triple negative breast cancer (TNBC), which displays a poor prognosis.
Methods/Results: In two murine models of TNBC (4T1 which is highly metastatic and 67NR which is locally aggressive), mice with palpable tumors were treated with radiation, caloric restriction (30% intake reduction) or both. 3 times per week measurements revealed significant tumor regression with RT or diet modification, and an even greater regression is observed combining diet modification with RT. Concurrently, many reports have shown that TNBC is most distinct from other breast tumor subtypes due to up-regulation of the miR-17-92 cluster which we have shown by RT-PCR is downregulated with both CR and radiation (RT) and even further decreased with the combination. cDNA arrays done on all conditions revealed that the top 5 statistically significant GO terms with high fold changes were all associated with extracellular matrix and metastases. In silico analysis demonstrated 5 ECM related genes that were targets of the miR-17 cluster: collagen 4 alpha 1 (COL4A1), collagen 4 alpha 3 (COL4A3), laminin alpha 3 (LAMA3), metallopeptidase inhibitor 2 and 3 (TIMP2 and TIMP3) and these were inversely correlated with the miRs.
Conclusions: CR, or altering the metabolism of breast cancer, can be combined with RT to decrease progression of TNBC tumors and that the miR-17-92 cluster is also decreased with these conditions. cDNA arrays suggest that extracellular matrix (ECM) proteins play a large role in the mechanism of action of CR and RT combined. Combination therapy with CR and RT can decrease the metastatic potential in TNBC and in part does this through the miR-17-92 cluster by way of controlling ECM.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-01-03.
Abstract P6-01-04: DDB2 a new regulator of metabolism and cell death in human breast tumor cells
Authors: Klotz R , Besancenot V , Brunner E , Becuwe P , Grandemange S 
Published: August 2014

Abstract
The protein Damaged DNA Binding-2 (DDB2) is well known for its role in DNA repair by nucleotide excision repair. Interestingly, DDB2 is differentially expressed in breast cancer expressing the estrogen receptor alpha or not. Recent works performed in our laboratory showed a new role of DDB2 in the control of proliferation and invasive abilities in different breast tumor cells through its involvement in the transcriptional regulation of target genes. Two genes involved in tumorigenic processes, MnSOD (manganese superoxide dismutase) and IκBα (inhibitor alpha of Nuclear Factor-kappa B), have been found to be regulated by DDB2. In addition, transcriptomic analyses on cells that differentially express DDB2 showed that several genes involved in the regulation of cellular metabolism are modulated. Our aim is now to focus on the effects of DDB2 expression on cellular metabolism and glycolysis. The results indicated that the overexpression of DDB2 leads to a respiratory chain dysfunction and an increase of the glycolytic pathway. Moreover, we observed an increased production of reactive oxygen species in these cells, compared to parental cells. As mitochondria are involved in cell death, we performed different experiments to evaluate the impact of DDB2 in the response to anticancer agents (Doxorubicin, and 5-fluorouracile (5-FU)) commonly used in the treatment of breast cancer. Interestingly, the cells exhibit a greater sensitivity to anticancer drugs when DDB2 is overexpressed. As these two agents are related to DNA damaged, we have also used other molecules, the apoptotic inducer, TNFα (Tumor Necrosis Factor alpha), and the Paclitaxel (an antimicrotubule agent) to precise the role of DDB2 on cell death. Similar results were obtained, thus demonstrating the influence of DDB2 overexpression in the response to cell death. The identification of molecular mechanisms responsible for these cellular modifications could place DDB2 and these target genes as predictive markers of sensitivity to anticancer drugs in breast cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-01-04.