bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-10-01: A randomized phase 2 study of the antibody-drug conjugate CDX-011 in advanced GPNMB-overexpressing breast cancer: The EMERGE study
Authors: Yardley DA , Weaver R , Melisko ME , Saleh MN , Arena FP , Forero A , Cigler T , Stopeck A , Citron D , Oliff I , Bechhold R , Loutfi R , Garcia A , Crowley E , Green J , Yellin MJ , Davis TA , Vahdat LT 
Published: August 2014

Abstract
Background: GPNMB is an internalizable transmembrane glycoprotein overexpressed in multiple tumor types, including breast cancer (BC). GPNMB promotes BC metastases in a murine model and is a poor prognostic marker in patients (pts) (Rose 2010). CDX-011 (glembatumumab vedotin) is a fully human GPNMB-specific monoclonal antibody conjugated to the potent cellular toxin MMAE via a protease-sensitive peptide linker, designed to cleave upon cellular internalization. In Phase I/II studies of CDX-011 in BC (n = 42), an objective response rate (ORR) (including confirmed and unconfirmed response) of 12% overall and 20% for “triple-negative” (ER/PR/HER2−; TN) pts was observed (Saleh, ASCO 2010).
Methods: The Phase II EMERGE study examined the efficacy of CDX-011 by level of GPNMB expression. Refractory BC (2–7 prior cytotoxic regimens in metastatic setting), GPNMB expression in ≥ 5% of tumor or stroma cells (as centrally determined on archival tumor), and no persistent treatment-related toxicity (including neuropathy) of ≥ Grade 2 severity were required for enrollment. Pts were stratified by GPNMB expression pattern (any tumor, low stromal or high stromal) and randomized 2:1 to CDX-011 (1.88 mg/kg IV q 21 days) or “investigator's choice” (IC) single-agent chemotherapy, and treated until progression (PD) or intolerance with IC pt crossover permitted to CDX-011 at PD. Endpoints: ORR (primary), progression-free survival (PFS), safety, pharmacokinetics, pharmacodynamics.
Results: 99% of screened tumor samples expressed GPNMB. 122 treated pts (81 CDX-011 vs. 41 IC) had median age = 56 vs. 56 years; median # prior anticancer regimens = 6 vs. 5; visceral disease (liver/lung) = 83% vs. 80%; TN = 33% vs 27%, respectively. To date, 15 IC pts have crossed over to CDX-011, and 14 pts (8 CDX-011, 6 IC) continue on treatment. CDX-011 was well tolerated with less hematologic toxicity than IC; CDX-011-related toxicity included rash (overall = 38%; Grade 1 = 20%; Grade 2 = 15%; Grade 3 = 3%) and neuropathy (overall = 18%; Grade 1 = 8%; Grade 2 = 7%; Grade 3 = 2%).

Conclusions: CDX-011 was a well-tolerated and active agent in this heavily pre-treated BC pt population. Preliminary analysis of the EMERGE study demonstrates enhanced activity of CDX-011 in TN as well as high GPNMB expressing BC tumors, confirming that CDX-011 is a targeted agent. This noted promising activity in advanced TN and hGPNMB enriched pt populations warrants further evaluation.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-10-01.
Abstract PD03-08: Statin use and improved outcome in primary inflammatory breast cancer: retrospective cohort study
Authors: Brewer TM , Masuda H , Iwamoto T , Liu P , Shen Y , Liu DD , Kai K , Barnett CM , Woodward WA , Reuben JM , Yang P , Hortobagyi GN , Ueno NT 
Published: August 2014

Abstract
Background Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer. HMG-CoA reductase inhibitors (statins) are cholesterol reducing agents with pleiotropic effects, including antitumorigenic and anti-inflammatory properties. We hypothesized that statins reduce the metastatic potential in primary IBC.
Methods We retrospectively reviewed 724 patients diagnosed with and treated for primary IBC at The University of Texas MD Anderson Cancer Center between Jan. 12, 1995 and Jan. 27, 2011. Patients with records indicating statin use at the time of IBC diagnosis on the electronic medical record were compared with those without. We further compared outcomes stratified by statin type (hydrophilic [H] versus lipophilic [L]). We used the Kaplan-Meier method to estimate the median disease-free survival (DFS) after surgery, overall survival (OS), and disease specific survival (DSS), followed by Cox proportional hazards regression model to test statistical significance of several potential prognostic factors.
Results For primary IBC patients who had information on their statin use status at IBC diagnosis, the median DFS time were 4.88 years, 2.47 years and 1.76 years (P= 0.04); the median OS time 5.05 years, 3.79 years and 4.32 years (P= 0.35); and the median DSS time 5.10 years, 3.79 years and 4.52 years (P= 0.37), for patients who took “ H”, “L” and no statin, respectively. In multivariable Cox model stratified by radiation therapy, ER/PR status and HER2 status, statin “H” use was associated with significantly improved DFS compared to no statin use (HR=0.49; 95% CI: 0.28–0.84; p&lt;0.01), adjusted for lymphatic/vascular invasion. Although there is a trend that patients who used statin “H” had a longer time to death compared to patients who did not take statin, it did not reach statistical significance for OS (HR=0.80; 95% CI: 0.43–1.49; p=0.49) and DSS (HR=0.85; 95% CI: 0.46–1.57, p=0.59) after adjustment for lymphatic/vascular invasion, nuclear grade and surgery status within one year.
Conclusions Hydrophilic statin use was associated with improved DFS. There was a trend for reduced HR in OS and DSS among primary IBC patient who used hydrophilic statins. A prospective randomized study to evaluate the potential survival benefits of statins in primary IBC population is warranted.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-08.
Abstract ES01-1: Targeting the DNA damage response in triple negative breast cancer
Authors: Cortez D 
Published: August 2014

Abstract
Triple negative breast cancer (TNBC) comprises approximately 25 percent of breast cancer deaths. There is a critical need to develop better therapeutic options for TNBC patients. We hypothesize that at least a subset of these cancers are especially dependent on DNA repair mechanisms that are coordinated by the ATR kinase-dependent DNA damage response signaling pathway. This hypothesis has been tested using genetic and chemical genetic approaches. We are working to develop small molecule inhibitors of the ATR pathway, understand how they work, and identify when these targeted therapies may provide clinical benefit. Our studies of an ATR selective inhibitor indicate that it kills cells due to a requirement for ATR signaling to complete DNA replication. ATR inhibition is synergistic with other chemotherapeutic agents such as platinum crosslinking drugs. ATR-inhibitor treated cells accumulate toxic DNA double-strand breaks and large stretches of single-stranded DNA through an active process catalyzed by deregulated nucleases and helicases. Effective biomarkers of ATR inhibition include DNA-PK, H2AX, RPA, and ATR phosphorylation. We have also worked with colleagues at Vanderbilt Medical School to identify additional therapeutic targets and develop small molecule inhibitors.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES01-1.
Abstract ES01-2: 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions
Authors: Nussenzweig A , Callen E 
Published: August 2014

Abstract
The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination (HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions of 53BP1 are mediated in part by RIF1, the only known factor that requires 53BP1 phosphorylation for its recruitment to double-strand breaks (DSBs). Here, we show that a 53BP1 phosphomutant, 53BP1(8A), comprising alanine substitutions of the eight most N-terminal S/TQ phosphorylation sites, mimics 53BP1 deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP1(8A) recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP1(8A). We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES01-2.
Abstract ES02-2: Who should receive preventive therapy?
Authors: Cuzick J 
Published: August 2014

Abstract
Several options are now becoming available for preventive therapy in women at increased risk for breast cancer. A major challenge is to determine which women are at sufficiently high risk to warrant treatment, and who will benefit from such treatment. Standard risk factors have been combined in several models to develop a risk score, and the spread in 10-year risk associated with these models will be examined. Two new features which offer improved prognostic discrimination are breast density and SNP profiles. The former can be routinely read visually, but there is a substantial inter-reader variability, and a goal is to develop automated testing which is reproducible and highly prognostic for risk. SNP profiles consist of panels (now over 70) of low risk but common genes that individually are not useful, but as a panel may add useful information. A discussion of the relative amount of information in classic models, mammographic density, and SNP scores will be presented along with initial estimates of their combined utility. Lastly we look at markers which may be able to predict response to endocrine prophylactic treatment. Currently change in breast density offers the most promise in this arena.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES02-2.
Abstract ES03-3: Clinical 101: Clinical trial endpoints: Selection, analysis and interpretation
Authors: Garrett-Mayer E 
Published: August 2014

Abstract
The selection of clinical endpoints when designing a clinical trial is critically important to ensure appropriate evaluation of the agent or regimen of interest. Endpoints in early stage clinical trials differ from those in later stage trials, and the nature of the endpoints (e.g., continuou,s categorical) has an impact on both the parameters that can be estimated and the power to detect significant differences. This talk will focus on the selection of continuous (e.g. Ki67, breast density, change in tumor size), categorical (e.g. RECIST response, pathologic complete response), and time to event endpoints (e.g. progression-free survival, overall survival) when designing clinical trials. Discussion will also include interpretation of resulting measures of clinical efficacy (e.g. hazard ratios), approaches for stating trial objectives and implications of endpoint selection on statistical power.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES03-3.
Abstract ES07-2: Inflammatory breast cancer: Diagnosis, treatment and biology
Authors: Woodward WA 
Published: August 2014

Abstract
Inflammatory breast cancer (IBC) is a relatively rare variant of breast cancer accounting for a disproportionate amount of breast cancer mortality. It is histopathologically similar to non-IBC but presents with a very distinct clinical picture: rapid onset of breast redness and swelling often without an obvious lump. Misdiagnosis and delay in diagnosis are common. Although the breast appears “inflamed” obvious inflammatory infiltrates are not detectable in most tissues. Three presentations will focus on the diagnostic challenges, determinants, epidemiology, management and biology of inflammatory breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES07-2.
Abstract ES08-1: Imaging tumor response: Challenges of heterogeneity
Authors: Piwnica-Worms D 
Published: August 2014

Abstract
Large-scale sequencing analyses of solid cancers have identified extensive genetic inter-tumor and intra-tumor heterogeneity, which likely contribute to treatment failure and drug resistance. For example, recent unbiased whole genome sequencing approaches have highlighted the complexity of the mutational landscape of ER+ luminal breast cancers. In 46 breast tumors, 82,000 total somatic mutations and 2,000 tier 1 mutations were identified. While pathway signatures enabled the evaluation of mutations with low recurrence frequency where statistical comparisons conventionally were underpowered, this massive heterogeneity presents an enormous challenge for therapy and prognostic assessment of cancer. Furthermore, cells have evolved complex molecular networks to sense cues from the environment and transmit them throughout the cell to elicit appropriate biological responses. These signaling pathways require certain elemental properties, such as sensitivity, reversibility, a capacity to be regulated, and robustness, that are crucial to reliably maintaining the organization and function of cells within organisms. These molecular networks comprise sets of recurring regulation patterns, manifest as network motifs, which link together in a variety of combinations to create a web of connectivity within a given signaling pathway or between multiple cascades. Using a kB5-IkBα-FLuc bioluminescent reporter as one example, we rigorously evaluated the dynamics of IkBa degradation and subsequent NF-kB transcriptional activity in response to diverse modes of TNFα stimulation in isogenic tumor cells. Tremendous heterogeneity in the transcriptional amplitudes of responding cells was observed, which was greater than the heterogeneity in the transcriptional kinetics of responsive cells. Thus, systems heterogeneity was observed even in isogenic cells, further adding to the complexity of cellular responses and their associated signaling networks. One must conclude that inter-tumor and intra-tumor heterogeneity at the level of cancer genes and systems responses may have important consequences for targeted molecular imaging strategies that commonly lack spatial and temporal resolution in their depiction of tumor phenotypes.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES08-1.
Abstract ES09-1: Update on management of ER positive metastatic breast cancer
Authors: Burstein HJ 
Published: August 2014

Abstract
Patients with ER positive, metastatic breast cancer are candidate for endocrine and chemotherapy treatments in order to prolong survival, alleviate and forestall symptoms, and preserve quality of life. Classical management strategies such as the prompt initiation of ovarian suppression at the time of diagnosis of metastatic disease, the sequential use of treatment with endocrine agents and chemotherapeutic agents, the predilection of ER positive tumors for bone / soft tissue / mucosal and lymph nodes as initial sites of metastatic disease, and the lack of close correlation between clinical benefit and overt treatment response to endocrine agents remain valuable observations. Despite decades of clinical use, important new findings regarding endocrine therapy continue to emerge. Several examples of recent innovation include the following. 1. Dosing of fulvestrant. Because of limited bioavailability in its injectable formulation, higher doses of fulvestrant (500 mg) yield superior clinical outcomes than seen with the lower doses (250 mg) originally used for drug approval. 2. Combinations of aromatase inhibitors and fulvestrant. Historically, single-agent endocrine treatment has been the norm. Recent studies have examined AI therapy given with or without fulvestrant. In the FACT trial, no substantial benefit was observed. However, in the SWOG 0221 study, the combination led to improved overall survival, perhaps because this patient population had received less in the way of prior endocrine treatment. 3. Novel pathways: mTOR inhibitors. Everolimus, the orally available mTOR inhibitor, is now FDA approved for use in AI-refractory breast cancer based on the BOLERO-2 study which showed that adding everolimus improved PFS compared to ongoing AI therapy, alone. To date, genomic biomarkers have not lent themselves to clinical use for patient selection of mTOR inhibitor therapy. 4. Novel pathways: CDK4/6 inhibitors. Novel agents are targeting the CDK4/6 pathway in ER+ metastatic breast cancer, and show early promise in randomized phase II studies. 5. Use of estrogens as treatment for advanced breast cancer. Harkening back to observations from the 1950s and 1960s, investigators have shown in small phase II trials that estrogen therapy itself can achieve tumor regression and clinical benefit in ER+ metastatic breast cancer. 6. Genomic revolution. Full genome sequencing is now available for many ER+ advanced cancers, identifying frequent mtuations in many genes (PIK3CA, FGFR, IGFR, AKT, CCND1 and other genes that may lend themselves to targeted therapeutic approaches. In addition to these innovations in targeted the ER and related pathways, it is also becoming clear chemotherapy outcomes for women with ER+ breast cancer are effective, and often more effective than in the treatment of TNBC which is more often considered a “chemotherapy-treated” tumor. These advances and other insights into ER positive metastatic breast cancer will be discussed.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES09-1.
Abstract OT1-1-03: A phase 3 randomized, double-blind trial comparing PF-05280014 + paclitaxel vs. trastuzumab + paclitaxel for treatment of HER2+ metastatic breast cancer patients
Authors: Ewesuedo R , Barker KB , Taylor CT , Jacobs I 
Published: August 2014

Abstract
Background: PF05280014 is being developed as a potential biosimilar to trastuzumab. PF-05280014 demonstrated similarity to trastuzumab in nonclinical evaluations. In a Phase I trial in healthy volunteers, PF-05280014 pharmacokinetic characteristics and safety profile were shown to be similar to those of trastuzumab. The goal of this Phase 3 trial is to demonstrate that the efficacy and safety of PF-05280014 + paclitaxel are similar to those of trastuzumab sourced from the EU (trastuzumab-EU) + paclitaxel in women with HER2-positive metastatic breast cancer.
Trial design: In this randomized, double-blind trial, patients will be randomized 1:1 into 2 arms: PF-05280014 + paclitaxel and trastuzumab-EU + paclitaxel. Randomization will be stratified by prior adjuvant trastuzumab exposure and estrogen receptor status. The order of infusion will be PF-05280014 or trastuzumab (4 mg/kg in Cycle 1; 2 mg/kg thereafter over 90 min) first followed by paclitaxel (80 mg/m2).
Eligibility: Female patients, aged ≥18 y with confirmed HER-2 overexpressing metastatic breast cancer, ≥1measurable lesion (RECIST), Eastern Cooperative Oncology Group status 0–2, normal left ventricular ejection fraction, and normal laboratory values are eligible. Key exclusion criteria are prior systemic therapy for metastatic disease, prior cumulative dose of anthracyclines &gt;400 mg/m2, and major surgery, radiotherapy or investigational agents within 4 weeks. All subjects must provide informed consent.
Aims: The primary objective is to demonstrate the similarity in objective response rate (ORR) of PF-05280014 + paclitaxel treatment to that of trastuzumab-EU + paclitaxel. Secondary objectives include evaluating 1-year progression-free survival, safety, pharmacokinetics, and immunogenicity of these combination treatments.
Statistical methods: This study tests whether the ORR of PF-05280014 is similar to that of trastuzumab-EU, using a margin of 13%, i.e., 5% alpha for non-inferiority. Assuming 60% ORR in both arms, 600 patients (300/arm) will be needed to achieve 90% power. Assuming 10% attrition, a total of 660 patients will be randomized. The intent-to-treat (ITT) population is defined as all subjects who are randomized to receive treatment. The per-protocol population is defined as all subjects who are randomized to and receive treatment and do not have any major protocol violations and will be used for evaluation efficacy endpoints.
Accrual: The target accrual of this global trial is 660 patients.
Contact information: For further information, please contact the Director, Clinical Trials Disclosure Group, Pfizer Inc. (marla.brickman@pfizer.com).
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-03.
Abstract OT2-6-13: A randomized phase 2 study of the triplet combination of ridaforolimus (RIDA), dalotuzumab (DALO) and exemestane (EX) compared to the ridaforolimus, exemestane doublet in high proliferation, estrogen receptor positive (ER+) advanced breast cancer
Authors: Rugo HS , Tredan O , Ro J , Morales SM , Musolina A , Afonso N , Ferreira M , Park KH , Cortes J , Tan AR , Blum JL , Eaton L , Mauro D , Gause C , Im E , Baselga J 
Published: August 2014

Abstract
Background: The clinical benefit of combination of mTOR inhibition and anti-hormonal therapy has been previously established and represents a new standard of care for patients with hormone receptor positive (HR+) advanced breast cancer (ABC). Preclinical evaluation of the mTOR pathway demonstrates that dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A completed phase 1 study of the combination of the mTOR inhibitor, RIDA and the anti-IGFR antibody, DALO demonstrated preliminary signals of anti-tumor activity. This was further evaluated in a recently completed phase 2 study of RIDA-DALO compared to exemestane in ER+ ABC. Final safety and efficacy results from that phase 2 study will be reported at this meeting (see Baselga et al). Building upon the clinical synergies of mTOR and EX as well as the biologic relationship of the mTOR and IGFR pathways, a clinical study has been initiated to evaluate the triplet combination of RIDA-DALO-EX compared to RIDA-EX. Methods: This is a multicenter, international, randomized phase 2 study of the triplet combination of RIDA (10 mg by mouth daily for 5 out of every 7 days), DALO (10 mg/kg IV weekly), and EX (25 mg QD) compared to RIDA (30 mg by mouth daily for 5 out of every 7 days) and EX (25 mg QD) in high KI67 (≥15%) expressing ER+, ABC. Approximately 84 patients will be randomized 1:1 to either triplet or doublet therapy. Key eligibility criteria include: HR+ and HER-2 negative measurable ABC, prior therapy with a non-steroidal aromatase inhibitor, and KI67 labeling index ≥15%. The primary endpoint of the study is progression free survival (PFS). Key secondary endpoints include evaluation of percent (%) reduction from baseline in the sum of imaging measurements (target lesion diameters or volumes) at 16 weeks between the two arms, and overall response rates. The sample size is event driven with a target of 38 PFS events, which provides approximately 80% power, at 1-sided alpha of 0.1, to detect a HR of 0.5, corresponding to an approximate 100% improvement in median PFS, from 10.6 to 21.2 months. Safety parameters or adverse experiences of special interest include hyperglycemia, stomatitis, mucosal inflammation, pneumonitis and hearing loss. Accrual has been completed with results expected in May 2014.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-13.