bluuebunny/crossref_metadata_2025_split huggingface dataset:
P1-12-20: The Safety and Tolerability of Vorinostat in Combination with Lapatinib in Advanced Solid Tumors.
Authors: Chumsri S , Tait NS , Medeiros MM , Bauer KS , Betts K-MT , Lewis JC , Bao T , Feigenberg SJ , Kesmodel SB , Stearns V , Edelman MJ , Sausville EA , Tkaczuk KHR 
Published: June 2012

Abstract
Background: Lapatinib has been previously shown to markedly decrease cancer stem cells (CSC) in HER2−positive breast cancer. In preclinical models, we have demonstrated that histone deacetylase inhibitors (HDACi) such as vorinostat can induce differentiation and decrease CSC. The combination of vorinostat and lapatinib is synergistic with a combination index of 0.32 (synergism if CI &lt;1). We therefore undertook a pilot study to evaluate the combination of these two drugs in advanced solid tumors.
Method: Patients were eligible if they were: age ≥ 18 years with incurable solid tumors, ECOG PS 0–2, adequate organ function, and no prior exposure to HDACi. The first 3 patients received lapatinib at the dose of 1,250 mg continuous daily and vorinostat 300 mg 4 days on 3 days off. The second dose level with lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days off were administered in 6 patients. Cycles were repeated every 21 days until disease progression. Echocardiogram and radiologic evaluation were performed every 12 weeks. During the first cycle, pharmacokinetic (PK) evaluation was performed on days 18 and 21.
Results: Nine consented patients (7 with metastatic breast cancer, 1 with non-small cell lung cancer, and 1 with thyroid cancer) have been enrolled with the median age of 52 (range 25–66). Patients received an average of 6 prior treatments (range 2–10). No dose limiting toxicity or drug related death have been observed. Grade 1–2 toxicities including diarrhea, fatigue, muscle cramps and stomatitis were observed. No grade 3 or 4 hepatic, renal or cardiac toxicity were observed (including no QTc prolongation and no significant reduction in the left ventricular ejection fraction). Patients have received the maximum of 7 cycles (median 3 cycles, range 2–7). Response: as of June 2011, 2 patients are still on treatment. Two patients achieved stable disease (triple negative metastatic breast cancer and HER2−positive breast cancer), 6 patients with progressive disease, and 1 patient is too early to evaluate for response. PK analysis will be presented at the time of the meeting.
Conclusions: The combination of vorinostat and lapatinib is tolerable and has some antitumor activity in heavily pretreated advanced solid tumors. A phase II study in HER2−positive metastatic breast cancer is underway with lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days off.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-20.
P1-12-21: Adjuvant Trastuzumab Treatment without Adjuvant Chemotherapy in Early Breast Cancer.
Authors: Dall P , Koch T , Lenzen G , Kuhn T , Hielscher C , Reichert D , Maasberg M , Ehscheidt P , Eustermann H , Fischer G 
Published: June 2012

Abstract
Background: Trastuzumab (T) is approved in most Western countries for the treatment of early, HER2+ breast cancer (BC) parallel or sequential to adjuvant chemotherapy (CT). Nevertheless, as in metastatic disease, the antibody seems to be used without chemotherapy in a selected group of HER2+ patients (pt). The purpose of this analysis is to characterize this subgroup as well as describe safety and efficacy outcome parameters in this German prospective observation trial.
Methods: At present, 2870 patients (pts) have been enrolled and documented in this ongoing non-interventional study from 270 German centers. At data base closure for this analysis, sufficient documentation was available from 2422 eligible pts.
Results: The proportion of pts receiving T without preceding or concomitant CT (noCT) was 180/2422 (7.4%). This subgroup was characterized by higher age (median 58 vs.56 in the CT group, p=0.0026; ≥70 years: 18%/10%), smaller primaries (pT1 49%/43%, p=0.11), more favorable grading (G3 45%/53%, p=0.045), a higher proportion of positive hormone receptor (67%/61%, p=0.096) and less radiotherapy (64%/79%, p&lt;0.0001). The strong association to radiotherapy is probably due to the fact, that the choice of this additional modality reflects the overall risk assessment of the pt.
In contrast, there was no difference in nodal involvement (pN0: 52%/51%; positive nodes: mean 2.5/2.4). In multivariate analysis (logistic regression model, not incorporating radiotherapy), hormone receptor status is not predictive (p=0.41), while age ≥65 (p=0.0011), grade 1/2 (p=0.046) and pT1 (p=0.089) independently remain at least borderline significant. The mean number of T administrations was 18 and the median duration of T therapy was 12 months in the noCT group as well as the CT group. 57% of the noCT pts received adjuvant endocrine therapy. In the CT group, 81% received anthracyclines and 61% taxanes.
Based on a still low number of only 13 observed events in the noCT group, no differences in relapse-free survival could be detected (p=0.38). Pathological cardiac findings in the pt's history was not predictive of therapy selection (6%/7%) and were also similarly distributed at the end of T therapy (7%/8%). Cardiac function disorders of CTC grade 3/4 were reported in 1% of both groups, across all grades slightly less frequent in the noCT group (2.8%/4.0%).
Conclusions: A small, but distinct group of early BC pts without adjuvant chemotherapy receives T treatment for HER2+ disease. These patients are characterized by higher age and favorable primary tumor staging and grading, but not by cardiac comorbidities.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-21.
P1-12-26: Global Patterns of Care for HER2/Neu Overexpressing Breast Cancer.
Authors: Chavarri-Guerra Y , Liedke P , Symecko H , Moy B , Higgins M , St. Louis J , Finkelstein D , Goss P 
Published: June 2012

Abstract
Background: Her2/neu overexpression is an independent adverse prognostic factor present in approximately 25% of invasive breast cancers. HER2−overexpressing breast cancer is particularly common in younger patients and therefore poses a significant public health burden. Anti-Her2/neu adjuvant trastuzumab significantly reduces the risk of recurrence as well as improves survival. In view of the serious potential ramifications of not receiving anti-Her2/neu therapy when appropriate, we undertook this international project to determine clinical access to Her2/neu testing and treatment patterns for women with HER2/neu-positive early breast cancer.
Methods: A web-based survey was sent to 386 physicians from 33 countries who participated in the “TEACH” trial, a double blind placebo-controlled phase III study of a novel anti-Her2/neu therapy, lapatinib, in women with primary Her2/neu-positive breast cancer. The survey contained 27 questions addressing physician and patient demographics, access to Her-2/Neu testing in everyday clinical practice, and anti-Her2/neu treatment options in a variety of clinical scenarios.
Results: One hundred and fifty one participants (39%) from 28 countries answered the survey. Ninety eight percent of the participants reported having Her2/neu tumor expression routinely measured for clinical practice in their institutions by immunohistochemistry (83%), FISH (78%) and other methods (17%). Among Asian physicians, 18% did not have routine testing available and sent primary tumors for central testing for TEACH eligibility. Forty eight percent of physicians surveyed reported instances when they had recommended adjuvant Her2-directed therapy to a patient who eventually did not receive it. The proportion of physicians from developing countries that reported patients not receiving therapy was higher than those from developed countries (68% vs. 38%, respectively). The main reason for not receiving trastuzumab was cost in developing countries, while in more developed countries patient refusal and co-morbidities were the main reasons.
Discussion: This survey reflects availability of HER2 breast tumor testing and anti-Her2/neu therapy among physicians from 28 countries worldwide who participated in an anti-Her2/neu therapy clinical trial of a free anti-Her2/neu therapy. These results indicate that a high proportion of women with Her2/neu-overexpressing breast cancer may not receive standard anti-Her2/neu adjuvant therapy especially in developing countries, the barrier to treatment being cost of therapy. We are extending our access to care survey project to a more unselected diverse group of physicians in developing countries.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-26.
P1-14-01: Randomized Phase II Trial of Weekly vs. q 2-Weekly vs. q 3-Weekly Nanoparticle Albumin-Bound Paclitaxel with Bevacizumab as First-Line Therapy for Metastatic Breast Cancer.
Authors: Seidman AD , Conlin AK , Bach A , Forero-Torres A , Wright G , Hackney MH , Clawson A , Schofield D , Iglesias J , Hudis CA 
Published: June 2012

Abstract
Background: Nanoparticle albumin-bound paclitaxel (nab-P) 260 mg/m2 is superior to paclitaxel 175 mg/m2 (P) every 3 weeks (Gradishar et al. JCO 2005) in metastatic breast cancer (MBC), and weekly uninterrupted P is more effective than q3wk P in MBC (Seidman et al. JCO 2008). Bevacizumab (bev) nearly doubles response rate and time to progression (TTP) when added to P as 1st line therapy for MBC (Miller et al. NEJM 2007).
Methods: This open-label, phase II study randomized patients (pts) to nab-P at 260 mg/m2 q3wk (arm A) vs. 260 mg/m2 q 2wk with filgrastim (arm B) vs. 130 mg/m2 weekly uninterrupted (arm C), all with bev (15 mg/kg q 3 weeks arm A, 10 mg/kg q 2 weeks arms B and C). Patients were required to have measurable, HER2 negative MBC and no prior chemotherapy for MBC. The primary endpoints were response rate and toxicity.
Results: Of 212 pts randomized, 208 (75 arm A, 54 arm B, 79 arm C) were treated, with balanced demographics and baseline characteristics. The median age was 57 (range 29–85), 82% were postmenopausal and 89% had visceral disease (64% lung, 50% liver). ECOG PS 0:60%, 1:35%, 2:5%. 62% had prior neo-adjuvant or adjuvant chemotherapy for early stage disease: anthracycline: 54%, taxane: 38%. No significant differences in confirmed complete and partial response rates were noted (A: 40%, B: 44%, C: 46%). Median TTP was longer in Arm C (9.0 months) versus both arms B (6.3 months) and A (8.0 months), overall p=0.065. There were no differences in overall survival (Arm A: 21.3 months, Arm B: 19 months, Arm C: 25.3 months). As per protocol-specified stopping rule, arm B was closed early due to an unacceptable safety profile with significantly more grade ≥ 2 fatigue (B:57%, A: 39%, C:39%, p=0.048) and bone pain (B:19%, A:10%, C:4%, p=0.024). Sensory neuropathy was common; grades 2/3/4: Arm A: 29%/32%/1%, Arm B: 15%/50%/2%, Arm C: 27%/43%/1%). Sensory neuropathy was commonly readily reversible with dose delay and reduction. Febrile neutropenia occurred in &lt;2% of pts in all arms. Arm C patients experienced significantly less arthralgia compared with arms A and B, but dose delays were frequent (86% of pts) on this planned uninterrupted weekly schedule. Bevacizumab-related events were consistent with prior phase III trials of taxane/bev; there were no new safety signals.
Conclusions: Significant and similar antitumor activity was observed in all arms. Weekly nab-P with bev (arm C) resulted in longer TTP. Weekly nab-P with bev (arm C) appears to have the highest therapeutic index, however sensory neuropathy is limiting, suggesting that a 3 week on/1 week off schedule could be preferable and should be studied comparatively.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-14-01.
P1-14-04: Prolonged (≥1 Year) Exposure to First-Line Bevacizumab Combined with Paclitaxel in Patients with HER2−Negative Metastatic Breast Cancer Treated in a Routine Oncology Practice Study.
Authors: Kuemmel S , Schneeweiss A , Foerster FG , Geberth M , Tesch H , Klare P , Schumacher C , Hollburg W , Soeling U , Schmidt M 
Published: June 2012

Abstract
Background: First-line bevacizumab (BEV) combined with weekly paclitaxel (PAC) significantly improves progression-free survival (PFS) and response rate (RR) vs PAC alone in HER2−negative metastatic breast cancer (mBC), as shown in E2100. The benefit of BEV combined with other chemotherapy (CT) agents was demonstrated in AVADO and RIBBON-1. BEV was continued for ≥1 year in 21% of patients in the global ATHENA safety study and in 42% of patients in the JO19901 single-arm Japanese study of BEV-PAC. We analyzed data from the subgroup of patients treated for ≥1 year in a German routine oncology practice study to provide insight into the safety and efficacy of prolonged first-line BEV-PAC.
Methods: Patients who had received no prior CT for their mBC received BEV-PAC per the European label. Efficacy and safety were documented for up to 1 year (or until progression, death, or BEV discontinuation if earlier) with additional long-term follow-up. Data from patients treated with BEV for ≥1 year were extracted for this analysis.
Results: By Jan 2011, data were available for 818 patients, of whom 157 (19%) had already received BEV for ≥1 year. Baseline characteristics of this subset relative to the overall population are summarized in the table.

In 79% of those treated for ≥1 year, BEV was continued as a single agent after discontinuation of CT. The overall RR in patients treated for ≥1 year was 81% (complete response in 20%). Median PFS was 17.9 months (events in 44% of patients) vs 9.4 months in the overall population (events in 68%). Overall survival data are immature, as 81% of those treated for ≥1 year are still alive. The most common grade 3/4 adverse events in patients treated with BEV for ≥1 year were hypertension (11% of patients), pain (10%), and leukopenia (7%). There were no cases of gastrointestinal perforation, arterial thromboembolic event, or reversible posterior leukoencephalopathy syndrome in those treated for≥1 year. Analysis of adverse events according to time of onset is ongoing.
Conclusions: A notable proportion of patients appear to derive benefit from prolonged exposure to first-line BEV-containing therapy. In the present analysis, baseline characteristics appeared more favorable in the subset of patients treated for ≥1 year than in the overall population. Efficacy data clearly have a bias towards improved outcome in those able to continue BEV for ≥1 year, as these patients had sustained disease control for ≥1 year. However, the efficacy of prolonged BEV-containing therapy is of interest and suggests that some patients achieve sustained disease control with continued first-line BEV-PAC with limited side effects.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-14-04.
P2-01-18: Cancer Stem-Like Cells in Breast Cancer Progression.
Authors: Valejo FAM , Andrade JM , Sicchieri RD , Antonio HMR , Marana HRC , Mouro LR , Oliveira TMG , Benevides L , Silva JS , Muglia VF , Tiezzi DG 
Published: June 2012

Abstract
Background: increasing evidences support the presence of cancer stem-like cells (CSLCs) within breast carcinomas. A subset of cells enriched for CSLCs within the tumor can be identified by flow cytometry. It has been supposed that CSLC component is responsible for tumor resistance and metastasis. However, the analysis of such population has never been evaluated during breast cancer progression. Patients and Methods: We prospectively included 98 women with histologically proven breast carcinomas to assess the presence of CSLCs within the primary tumor. According to clinical stage (CS), five patients were CS 0 (palpable DCIS), 16 CS I, 20 CS II and negative lymph nodes (IIA-), 20 CS II and positive lymph nodes (IIA+), 6 IIIa, 17 IIIb, 1IIIc and 2 CS IV. Additionally, ten lymph node metastases from IIA+ patients were analyzed. Invasive ductal carcinoma (IDC) was observed in 79 patients. We excluded from the analysis patients with non ductal histology (n= 11). The percentage of CD44+/CD24- (n= 79), ALDH1+ (ALDEFLUOR®) (n= 29), ABCG2+ (n= 44) and CXCR4+ (n= 46) cells within ESA+ cells was determined by flow cytometry in fresh sampled tumors. The mammosphere assay was studied in 14 samples. The relationship between cytometry analyses and clinical and pathological features was analyzed.
Results: The median prevalence of CD44+/CD24- cells within ESA+ population was 1.63% in stage 0, 2.39% in stage I, 0.42% in stage IIA-, 8.15% in stage IIA+, 0.52% in stage III (p=0.005). The CD44+/CD24- cell population was analyzed in 10 lymph node metastasis and, the median prevalence of this population within ESA+ cells was 4.7%. There was no variation of median prevalence of ALDH1+, CXCR4+, ABCG2+ and the median number of spheres among clinical stages (p=0.1, p=0.8, p=0.8, p=0.8, respectively). We didn't observe any association among the expression of, ABCG2+, CXCR4+ with histological grade and the expression of ER and PgR. The median percentage of CD44+/CD24- cells was higher (2.39% vs 0.41%) in ER positive tumors (p=0.003). The median percentage of ESA+/ CXCR4+ cells was higher (42,5% vs 9,7%) in HER2− tumors. There was no correlation between the studied markers and the patients’ age and clinical tumor diameter. The results are summarized in Table 1.
Results of association between expression cells surface markers and ALDH1 activity (Aldefluor®) with clinical and pathological features in invasive ductal carcinomas.

Discussion: We found a significant variation in CSLC population during breast cancer progression. Our data show a gradual increase in CD44+/CD24- cells within ESA+ population from stage 0 to stage IIA+ and a significant decrease in stage III tumors. This observation supports the hypothesis that a population of CSLCs could be associated with breast cancer progression.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-18.
P2-01-22: Characterization of Four ER-Negative Breast Primary Tumor Dissociated Cultures as a Model for the In Vitro and In Vivo Study of Tumorigenesis, Metastasis and Angiogenesis.
Authors: Drews-Elger K , Brinkman JA , Dean SJ , El-Ashry D 
Published: June 2012

Abstract
ER negative breast cancers comprise a subtype of tumors for which there are few therapies with successful response. Currently, the use of established cell lines has allowed detailed molecular and cellular studies on cancer mechanisms ranging form stem cells to proliferation, from tumorigenesis to invasion and metastases, and from tumor suppressors to oncogenes. But while cell lines provide a source of homogeneous, propagatable material, a drawback of this model is that most breast cancer cell lines are derived from metastatic lesions that may harbor additional mutations and have little resemblance with the primary tumor of origin. Additionally, the continuous passage of these cells over the last 20-plus years has given rise to well-established differences in growth rate, hormone receptor status, karyotype and clonogenicity. Our purpose here was to characterize four primary dissociated tumor (DT) cell cultures from ER- breast tumors, the establishment of which we had previously described, to determine if they could provide more accurate models for both in vitro and in vivo studies. These four DT cultures (DT16, DT22, DT25 and DT28) display a triple negative phenotype and were characterized by their genomic profile by the PAM50 predictor analysis as belonging to the basal (DT22, DT25 and DT28) and luminal B (DT16) subtypes. Of those cultures for which primary tumor sample was available, microarray gene expression profiling and cell line clustering analysis show the primary tumor and dissociated culture cluster together and to similar breast tumors. Interestingly, of the three basal DT cultures, DT22 clusters with Claudin-low tumors and cell lines. We have established that each of these 4 DTs are tumorigenic in the NOD/SCID mouse model, and are now assessing their metastatic potential. DT16 generated metastases in 25% of the mice (6 out of 24; two in liver, four in lymph node). DT22 generated highly vascularized tumors, which may provide a relevant model for study of the in vivo vascular recruitment process. In addition, we have analyzed and characterized the role of pivotal signaling pathways often deregulated in breast cancer such as EGFR, P-MAPK, PI3k/mTOR, p53, TGFb, Hedgehog, Notch, and Wnt in both the 2D culture as well as in sections of xenograft samples. Given that the scope of primary tumor heterogeneity and consequently the early stages of breast tumorigenesis are under-represented by current in vitro models in breast cancer research, the use of these DT cell cultures could more accurately recapitulate the disease in both the in vitro and in vivo settings.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-22.
P2-01-25: Truncated p110 ERBB2 (CTF611) Increases Migration and Invasion of Breast Epithelial Cells by Inhibiting STAT5b Activation.
Authors: Ward TM , Iorns E , Hoe N , Kim P , Singh S , Ernani V , Liu X , Jegg A-M , Gallas M , Lippman ME , Pegram MD 
Published: June 2012

Abstract
Background: Truncated ERBB2 receptors are present in a subset of human ERBB2+ amplified/overexpressing breast tumors, and are associated with trastuzumab resistance, metastasis, and poor clinical prognosis. However, whether truncated ERBB2 receptors are drivers of metastasis has not been well defined. In this study, we examined effects of full-length (p185) and truncated (p110) ERBB2 on the migration and invasion of human mammary epithelial cells, including HMLE and MCF10A cells.
Material and Methods: Recombinant p185 and p110 ERBB2 were stably expressed in human mammary epithelial cells (HMLE) and MCF10A cells via retroviral vector. Expression of comparable levels of p185 and p110 in cells was confirmed by western blot. The phosphorylation states of downstream signaling proteins including STAT5 were assayed via phosphoproteomics and Collaborative Enzyme Enhanced Reactive (CEER™) immunoassay. The effects of the p110 constructs on cell migration and invasion were investigated by transwell assays. shRNA-encoding lentivirus was used for specific silencing of STAT5b in HMLE cells, and STAT5b silencing was confirmed at the protein level using western blot.
Results and Discussion: Expression of p110 ERBB2 increased cell migration (HMLE, p = 0.04; MCF10A, p&lt; 0.01) and invasion (HMLE, p= 0.03) when compared to expression of p185. Furthermore, expression of p110 in HMLE cells was associated with reduced phosphorylation of STAT5b. shRNA mediated silencing of STAT5b was sufficient to increase the migration (p &lt; 0.01) and invasion of HMLE cells, phenocopying the p110 driven effects on HMLE cells. In clinical studies, loss of activated STAT5 protein correlates with breast cancer progression and is a negative predictor of survival. By analyzing publicly available gene expression datasets, we found that STAT5b mRNA expression is also significantly decreased in breast cancer compared to normal breast tissues in several studies, as well as in ERBB2 amplified vs. nonamplified samples. To our knowledge, this is the first reported perturbation of STAT signaling by truncated ERBB2 receptor, and suggests a mechanism by which truncated p110 ERBB2 (CTF611) increases migration and invasion of breast epithelial cells. This study extends the available data regarding STAT5 loss in breast cancer progression.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-25.