bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-13-07: Clinicopathologic and Biologic Recurrence Risk in African-American Versus Caucasian Women with Early-Stage Hormone Receptor Positive Breast Cancer, a Single Institution Experience
Authors: Allen AD , Allen JW , Sachdev JC. 
Published: April 2011

Abstract
Background: African-American women with hormone receptor positive breast cancer have an inferior survival compared to Caucasians (Sparano, et al (SABCS, 2009, Abstract #37) and Albain, et al (ASCO, 2010, Abstract #511)). It is not clear whether this difference is a result of disparities in access to care and stage at presentation or biological factors. We sought to examine whether African-American women with early-stage hormonereceptor positive breast cancer had a higher risk of recurrence than similarly staged Caucasians using a standard clinicopathologic risk prediction algorithm (AdjuvantOnline!) and a biologic risk prediction algorithm (Oncotype DX).
Materials and Methods: Women with early stage, hormone receptor positive, Her2 normal, lymph node negative breast cancer seen at the University of Tennessee Cancer Institute between 2007-2009 were retrospectively reviewed. All patients had an AdjuvantOnline! recurrence risk calculated. For patients in whom an Oncotype DX was available, differences in risk of recurrence between clinicopathologic and biologic algorithms were evaluated with respect to race (African-American versus Caucasian).
Results: 96 women were identified, 38 of whom were African-American and 58 of whom were Caucasian. 50 women had an Oncotype DX available. Clinicopathologic factors were well-balanced between the groups (see Table 1). Using AdjuvantOnline!, there was no significant difference between African-American and Caucasian patients in their average risk of recurrence (25% versus 23%, P=0.15). Using Oncotype DX, there was similarly no significant difference in the average risk of recurrence by race (18.6% for African-American versus 18.9% for Caucasian, P=0.55).
Patient Characteristics
Grade was not available for 1 Caucasian patient.
Discussion: When matched for stage and general clinicopathologic factors (hormone receptor positivity, Her2 normal, lymph node negative), African-American and Caucasian patients have similar risk of recurrence using AdjuvantOnline! and Oncotype DX, though the expected risk was somewhat lower with Oncotype DX in both groups. This would suggest that there may be little biologic difference between African-American and Caucasian women with early stage hormone receptor positive breast cancer and that any difference in survival is likely related to non-biological factors.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-13-07.
Abstract P3-14-09: Preclinical Safety and Activity of MM-302, a HER2-Targeted Liposomal Doxorubicin Designed To Have an Improved Safety and Efficacy Profile over Approved Anthracyclines
Authors: Wickham TJ , Reynolds J , Drummond DC , Kirpotin DB , Lahdenranta J , Leonard SC , Geretti E , Lee H , Klinz S , Hendriks BS , Olivier K , Eckelhofer I , Park JW , Benz CC , Moyo VM , Niyikiza C , Nielsen UB. 
Published: April 2011

Abstract
Background: Anthracyclines have been an effective backbone of breast cancer therapies for decades. However, cardiotoxicity issues associated with free anthracyclines have limited their effective use in the clinic and ledto the exploration of anthracycline-free regimens, particularly with HER2- positive cancers that require treatment with another cardiotoxic agent, trastuzumab. While liposomal doxorubicin formulations have succeeded in reducing cardiotoxicity, they have failed to demonstrate clearcut efficacy advantages and can involve other toxicities. To address the safety and efficacy limitations of currently available anthracyclines, we have designed a new liposomal formulation, MM-302, that targets doxorubicin to HER2- overexpressing tumor cells. Antibody fragments that bind to HER2 without blocking HER2-mediated signaling are coupled to the outer surface of pegylated liposomal doxorubicin. MM-302 specifically binds and enters tumor cells overexpressing HER2 with minimal uptake into normal cells such as cardiomyocytes which express low levels of HER2. Materials and methods: MM-302, untargeted pegylated liposomal doxorubicin (PLD), and free doxorubicin were compared for their uptake into target and nontarget cells, pharmacokinetics, biodistribution, tumor microdistribution using FACS and confocal microscopy, and anti-tumor activity in BT-474 and NCI-N87 xenograft models. Results: Cellular uptake studies in tumor cell lines expressing various levels of HER2 demonstrate that MM-302 delivers significantly higher doxorubicin levels to HER2 over-expressing tumor cells compared to PLD as well as similar or higher levels than highly permeable free doxorubicin. However, in human cardiomyocytes, while free doxorubicin was again taken up at high levels, doxorubicin uptake was dramatically lower with both MM-302 and PLD. Pharmacokinetic studies in mice demonstrate that MM-302 has a similar half life, clearance, and organ distribution compared to PLD. In HER2-overexpressing BT-474 breast and NCI-N87 gastric tumor xenografts, MM-302 exhibits superior anti-tumor activity to both free anthracyclines and PLD. Tumor microdistribution studies further suggest that differences in the localization of doxorubicin in the tumor may be responsible for the enhanced activity of MM-302 compared to free doxorubicin and PLD.
Discussion: These preclinical data suggest that MM-302 may provide in clinical practice a new opportunity to specifically deliver an anthracycline to HER2-overexpressing tumors with a potentially cleaner safety profile and improved efficacy over currently available free or liposomal doxorubicin.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-09.
Abstract P3-14-23: Affitoxin — A Potent Therapeutic Agent for Treatment of HER2- Overexpressing Tumors
Authors: Zielinski R , Lyakhov I , Hassan M , Kuban M , Shafer-Weaver K , Capala J. 
Published: April 2011

Abstract
Introduction: Cancers overexpressing HER2 gene are usually described as more aggressive and are associated with poor prognosis. Although introduction of trastuzumab, a HER2-specific humanized antibody, significantly improved the outcome, there are still number of patients who do not respond or acquire resistance to HER2-targeted therapy. We have previously described the construction, expression, and in vitro characterization of Affitoxin, a recombinant protein combining HER2- specific Affibody and modified Pseudomonas exotoxin A (PE 38) that blocks protein synthesis by ADP ribosylation of eEF-2 (Zielinski et al. 2009). In this report we present in vivo data.
Materials and Methods. Recombinant Affitoxins were expressed and purified from the soluble fraction of E.coli. HER2 specificity was confirmed in vitro by measurement of the residual ATP level in N87 cells treated with Affitoxin and “Non-specific” toxin. containing “off-target” instead of HER2 - Affibodies. Acute toxicity and immunogenicity studies were performed in female Balb/c mice. Affitoxin clearance rate was determined by ELISA and residual serum toxicity. Biodistribution in subcutaneous BT474 tumors model was determined by NIR optical imaging. In vivo efficacy of the drug was verified in subcutaneous (BT474, SKOV3) and intraperitoneal (SKOV3-luc-D3) tumor models.
Results. In this work we have confirmed that HER2-specific Affitoxin is a potent agent eliminating HER2-overexpressing cells in vitro at low picomolar concentration range, while non-specific toxin-containing offtarget Affitoxin is four orders of magnitude less efficient. Acute toxicity studies showed that Affitoxin is well tolerated by mice with LD50 = 0.572±0.051 mg/kg. Injection of six doses every third day neither lead to significant weigh loss of the animal nor induced severe liver problems. Pharmacokinetic data indicated fast clearance of Affitoxin from the circulation with half-life shorter than 10 min. Using human tumor xenograft models, we have shown that Affitoxin accumulates in HER2- overexpressing BT474 tumors, leading not only to reduction of growth rate but also permanent shrinkage of relatively large (&lt;1000mm3) xenografts. Treatment with non-specific toxin did not affect the BT474 tumors. Affitoxin was also shown to delay the growth of both SKOV3 subcutaneous and intraperitoneally spread tumors.
Immunogenicity studies indicated that Affitoxin is less immunogenic than toxin containing antibody fragments fused to PE38 (HA22).
Conclusions. Affitoxin is a novel recombinant protein, using high affinity Affibody molecules to target HER2 receptors. Our in vitro and in vivo data strongly suggest that Affitoxin might be an attractive alternative or complement for existing HER2 targeted therapies
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-23.
Abstract P3-14-24: Overall Survival Benefit Observed with Lapatinib (L) Plus Paclitaxel (P) as First-Line Therapy in Patients with HER2-Overexpressing Metastatic Breast Cancer (MBC)
Authors: Guan Z-z , Xu B-h , Arpornwirat W , Tong Z-s , Lorvidhaya V , Wang L , Newstat B , DeSilvio M , Moore Y , Shen Z-Z. 
Published: April 2011

Abstract
Background: Lapatinib (L) is a potent, oral selective, reversible, inhibitor of EGFR (ErbB1) and HER2 (ErbB2) receptor tyrosine kinases. EGF104535 is a phase III, international, randomized, double-blind study comparing lapatinib plus paclitaxel (L+P) versus P alone as 1st linetreatment for pts with HER2-positive+ (MBC). The study was focused in the Asia Pacific region.
Methods: Pts with centrally confirmed HER2-positive (by FISH) MBC and measurable disease were randomized to L 1500 mg daily + P 80mg/m2/wk 3 out of 4 wk or to P 80mg/m2/wk 3 out of 4 wk alone. Pts were administered P for 6 cycles with additional cycles at investigator discretion, and continued on blinded randomized therapy until disease progression (PD). At time of PD, there was an optional monotherapy extension to allow pts on P alone arm to receive L monotherapy. The primary endpoint of the study was overall survival (OS); secondary endpoints included progressionfree survival (PFS), overall response rate (ORR), clinical benefit rate (CBR) and safety. Analyses were conducted on the intent-to-treat population.
Results: 444 pts (N=222/arm) across 43 centers were randomized: 67% of P pts received L monotherapy. Baseline demographics were well-balanced between treatment groups. OS was significantly longer in the combination therapy (L+P) as compared with P alone. [Cox Regression Analysis: Treatment Hazard Ratio (HR) (95% CI)=0.64(0.49,0.82), p=0.0005, Kaplan-Meier estimates: median OS 27.8 mos (95% CI=23.2,32.2) vs 20.5 mos (95% CI=17.9,24.3), respectively]. Median PFS increased to 9.7 mos (95% CI=9.2, 11.1) compared with 6.5 mos (95% CI=5.5, 7.3), in the L+P vs P, respectively [HR (95%CI)=0.52(0.42,0.64), stratified log rank P&lt;0.0001]. ORR for L+P was 69% (95% CI=63%,75%) compared with 50% (95% CI=43%,56%) for P alone [Odds Ratio=2.3 (1.54, 3.47), P&lt;0.0001]. CBR improved with L+P (75%, 95% CI=69%,80%) compared with P alone (56%, 95% CI=49%,63%) [Odds Ratio=2.34 (1.54, 3.58), P&lt;0.0001]. The most frequent adverse events (AEs) were diarrhea (L+P, 77%, Grade 3/4 20/0; P, 29% Grade 3/4, &lt;1/&lt;1) and neutropenia (L+P, 77% Grade 3/4, 35/16; P, 47%, Grade 3/4, 15/5). The incidence of withdrawal from treatment due to AEs (13% vs 10%) was a similar. Conclusion: The combination of L+P showed a statistically and clinically meaningful survival advantage. Secondary endpoints support the observed clinical benefit. The combination of L+P was well tolerated.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-24.
Abstract P3-15-02: Underreporting of Myelotoxicity with Emerging Breast Cancer Regimens
Authors: Vandenberg T , Verma S , Loibl S , Crawford J , Choi MR , Dreiling L , Chan A. 
Published: April 2011

Abstract
Background: Although many emerging regimens that incorporate targeted agents may produce increased myelosuppressive side-effects, clinical data guiding colony-stimulating factor (CSF) use with these regimens are not readily available. This review assessed the reporting diligence around febrile neutropenia and the related use of CSF and antibiotics in published clinical trials evaluating emerging regimens for breast cancer treatment.
Methods: We searched Medline, EMBASE, and Cochrane databases to identify randomized, controlled phase 3 breast cancer studies published between Jan 2005 and June 2009. After excluding trials of vaccines, hormonal therapy alone, and stem cell transplantation/mobilization, corresponding publications were retrieved and data extracted on the incidence of neutropenia and its complications and CSF/antibiotic use. We then calculated the percentage of these publications that reported each outcome.
Results: Of 463 trials identified from the search, only 73 met the inclusion criteria. Overall, 70% and 55% of trials reported the incidence of grade 3/4 neutropenia and febrile neutropenia, respectively (Table). Neutropenia-related hospitalizations were reported in 3% of trials. Prophylactic use of CSF and antibiotics was defined in the methods section of 59% and 23% of trials, respectively; and only reported in the results section of 22% and 5% of trials, respectively.
Conclusion: Clinically significant neutropenia and neutropenia-related events (including febrile neutropenia) were generally described in the studies evaluated; however, the reported use of CSF and/or antibiotics was infrequent and inconsistent in the published literature of emerging regimens. A standardized approach to reporting neutropenic outcomes as well as the use of supportive care measures can assist cliniciansto prospectively manage the relevant toxicities associated with these emerging regimens and thereby facilitate their safe and effective use in clinical practice.
Table: Reporting of myelotoxicity data in published phase 3 trials
CSF = colony-stimulating factor

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-15-02.
Abstract P3-15-09: Symptomatic Congestive Heart Failure after Neo/Adjuvant Dose-Dense Epirubicin: A Retrospective Analysis of Two Trials with Long-Term Follow-Up
Authors: Gajria D , Pokuri V , Steingart R , Hudis C , Dang C. 
Published: April 2011

Abstract
Background:
Dose-dense (dd) anthracycline-taxane (A/T) based regimens (Rxs) have led to incremental benefits in breast cancer outcomes. Long-term incidence of symptomatic cardiac events for A/T Rxs (conventional and dd) has been ≥2.5%. The risk of long-term cardiac dysfunction related to total anthracycline dose and schedule remains a clinical concern. Additionally, the significance of asymptomatic short-term changes in left ventricular ejection fraction (LVEF) on the development of clinically significant congestive heart failure (CHF) is uncertain. Here we examine the incidence of symptomatic CHF, as per the New York Heart Association (NYHA) functional classification, for 82 patients (pts) exposed to neo/adjuvant dd epirubicin.
Methods:
We conducted a retrospective review of pts treated on two clinical trials: trial A-pts received fluorouracil, epirubicin, and cyclophosphamide (FEC) (500/100/500 mg/m2 every 2 weeks x 6) followed by weekly paclitaxel (80 mg/m2) alternating with docetaxel (35 mg/m2) x18; trial B-pts received EC (100/600 mg/m2 every 2 weeks x 6) followed by paclitaxel (175 mg/m2 every 2 weeks x 6). Total E dose was 600 mg/m2 for each trial. Pts with a known history of unstable angina, myocardial infarction, and/or CHF were excluded. All pts received a baseline LVEF evaluation, and in trial B pts received a repeat evaluation within 3 months after Rx completion.
Results:
Trial A enrolled 44 pts with a median age of 46 years (range, 26-63), 9 pts with pre-existing diagnosis of hypertension (HTN), and a median baseline LVEF of 66% (55-80%); 16/44 (36%) pts received left-sided radiation. At a median follow-up of 83 months, one patient (2.2%) developed NYHA class III CHF; 12 months after Rx completion her repeat LVEF was stable and 75 months after completion, an echocardiogram showed an LVEF of 21%.
Trial B enrolled 38 pts with a median age of 47 years (30-72), 5 pts with pre-existing HTN, and a median baseline LVEF of 69% (57-85%); 18/38 (47%) pts received left-sided radiation. Within 3 months of Rx completion, 28/38 (74%) pts had a repeat LVEF assessment with a median LVEF of 65% (40-76%). At a median follow-up of 56 months, one patient (2.6%) developed anthracycline-induced symptomatic class II CHF three months after Rx completion (baseline LVEF 61%, 3 months LVEF 42%). One patient (2.6%) suffered class III CHF one week after completing Rx with LVEF of 40%; this was in the setting of cocaine use and a repeat LVEF evaluation one month after the event showed a return to baseline LVEF. Overall, 2/82 (2.4%) pts had NYHA class III CHF.
Conclusion:
With long term follow-up our two studies demonstrate an acceptable 2.4% incidence of NYHA class III CHF after dose-dense epirubicin therapy. These findings are consistent with those of larger randomized trials evaluating the anthracyclines in breast cancer treatment.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-15-09.
Abstract P4-01-03: The Homeobox Protein H0XC10 Is Overexpressed in Breast Cancer and Confers Resistance to Chemotherapy
Authors: Sadik H , Shah N , Gupta RA , Chang HY , Sukumar S. 
Published: April 2011

Abstract
Background: Breast cancer is the second leading cause of cancer deaths in women worldwide. Although chemotherapy is effective, resistance to drugs develops over time and can account for treatment failure in over 90% of metastatic breast cancer patients. HOX genes are homeobox-containing transcription factors well-known for their role in morphogenesis. However, accumulating evidence has emphasized their importance during carcinogenesis and metastasis. The goal of this study is to understand the role of HOXC10 in breast cancer and the consequence of its overexpression in conferring chemotherapy resistance.
Methods: We conducted a tiling array of all four HOX clusters to identify dysregulated HOX genes in a panel of primary and metastatic breast cancer tissues, and validated the overexpression of HOXC10 in metastatic breast cancer. Next we established cell lines that stably overexpress HOXC10 and others where endogenously overexpressed HOXC10 was silenced by shRNAs, and determined phenotypic and biochemical changes resulting from these manipulations.
Results: HOXC10 is overexpressed in 67% of primary breast tumors (n=31), in 82% of the metastatic tissues (n=49) and in most breast cancer cell lines. When compared to cancers at other sites, overexpression tends to be significantly higher in breast cancer, and correlates with increasing grade and tumor size. Cell survival assays (MTT and colony formation) after drug treatment show that overexpression of exogenous HOXC10 in MCF10A conferred drug resistance. Further molecular examination revealed that overexpression of HOXC10 led to a dysregulation in the Rb-E2F pathway, and therefore the G1/S checkpoint was affected. In addition, the tendency for the formation of 8N cells and the concomitant protection from apoptosis suggested that HOXC10 overexpression might lead to genomic endoreduplication and instability. This fact along with the strikingenhanced recovery of the cells from pactitaxel treatment (as compared to the recovery from any other chemotherapeutic drug) and the protection from mitotic catastrophe implied a role of HOXC10 in the mitotic checkpoint. This was confirmed by a dysregulation of the expression of the genes involved in this checkpoint. All these experiments were further validated by stably expressing a shRNA to HOXC10 in SUM159 breast cancer cells with high endogenous HOXC10 levels. Conclusion: Our studies show for the first time that HOXC10, a homeobox protein previously shown to be regulated during the cell cycle and to have a positive effect on proliferation, is overexpressed in the majority of breast cancers. This upregulation may have some clinical implications since cells with higher expression of HOXC10 tend to have more invasive properties, more genomic instability, and are more resistant to some chemotherapy drugs.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-01-03.
Abstract P4-01-04: The Impact of the Retinoblastoma Tumor Suppressor Pathway in Her2 Positive Breast Cancer Pathogenesis and Therapeutic Response
Authors: Rivadeneira DB , Ertel A , Witkiewicz AK , Mercier I , Lisanti MP , Knudsen E. 
Published: April 2011

Abstract
Extensive studies have shown that breast cancer is associated with molecular aberrations that underlie the distinct subtypes of disease that exhibit differential prognosis and susceptibility to targeted therapeutic. A critical oncogenic event used to classify breast cancers is the amplification or overexpression of the human epidermal growth factor receptor 2 (Her2). Tumors harboring Her2 overexpression present aggressive characteristics related to metastatic spread and poor overall disease outcome. However, such tumors are also susceptible to targeted therapeutic agents which effectively impinge on this oncogene. Strikingly, those events that cooperate with Her2 and modulate susceptibility to targeted therapeutics remain poorly understood. Here the significance of the retinoblastoma tumor suppressor (RB) pathway in the context of Her2 positive breast cancer pathogenesis and therapeutic response was evaluated. In silico and histological analyses suggested that a subset of Her2 positive tumors exhibit compromised RB function. To model interactions between Her2 and the RB-pathway genetic deletion and knockdown strategies were employed in the context of Her2 driven tumors. These studies revealed that RB loss accelerated disease progression of such models and further enhanced the aggressive tumor phenotype.
To delineate the functionality of the RB-pathway downstream from therapeutic interventions targeting Her2, two complimentary approaches were used. First, the ability to effectively intercede in Her2-positive tumors using drugs that specifically activate the RB-pathway was interrogated. The data revealed that specific CDK4/6 targeted therapies were highly effective at limiting the growth of Her2-positive tumor cells. Second, the impact of RB status on the response the Her2/EGFR antagonist lapatinib was evaluated. These studies demonstrated that loss of RB compromises the effectiveness of lapatinib in the treatment of Her2 positive breast cancer cell lines. Ongoing studies are evaluating the spontaneous mechanisms of resistance to Her2 targeted therapeutics and the significance of reestablishing RB function as a therapeutic alternative in such cancers. Together, these studies underscore the importance of the interplay between Her2 signaling and cell cycle control in breast cancer, and how this crosstalk influences the response to targeted therapeutics in the treatment of breast cancer.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-01-04.