bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract BL-1: Brinker Award Lecture: How Does HER2 Contribute to Breast Cancer Progression?
Authors: Yarden Y 
Published: August 2014

Abstract
HER2 (also called NEU and ERBB2), a receptor tyrosine kinase frequently overexpressed in breast cancer, is one of the most oncogenic kinases of the human kinome. Multiple mechanisms contribute to the transforming potential of HER2. Although HER2 is structurally similar to the receptors for EGF (EGFR) and neuregulins (ERBB3 and ERBB4), the cytoplasm-facing kinase domain of HER2 is characterized by relatively high basal activity, and unlike the ectodomains of EGFR and ERBB3/ERBB4, HER2?s extracellular part cannot bind any known growth factor with high affinity. Nevertheless, HER2 acts as the preferred partner of the other three receptors, and the heterodimers it forms display not only high kinase activity but also increased binding affinity toward a broad spectrum of growth factors. In addition, HER2-containing heterodimers typically interact with a relatively wide set of cytoplasmic effector proteins, such as the phosphoinositol 3-kinase and SHC, which recruits the mitogen-activated protein kinase pathway. The collective outcome of these functional features translates to prolonged and enhanced signaling capacity.
One way to comprehend HER2 is offered by the evolutionary history of the family of receptor tyrosine kinases. Accordingly, HER2 and EGFR share a common precursor, but genome duplications denied a growth factor from HER2, and in parallel inactivated the catalytic function of ERBB3, to achieve a layered signaling network, whose autonomy and steady state are maintained by a dense web of feedback regulatory loops. In line with this scenario, HER2 cannot signal in isolation, but requires an activating growth factor receptor. Once recruited, HER2 enables evasion of negative feedback regulation, such as receptor ubiquitination and intracellular degradation: Unlike homodimers of EGFRs, which are targeted to lysosomes for degradation, HER2-containing heterodimers are targeted to a recycling pathway that replenishes the surface pool of HER2 molecules and further prolongs signaling.
In-depth understanding of HER2?s oncogenic functions holds promise for therapy of a fraction of breast cancer patients. For example, the relatively high basal activation of the kinase domain means that HER2 relies on a chaperone called HSP90, hence blocking HSP90 might retard HER2-overexpressing tumors. Likewise, it is predictable that agents able to block either recycling of HER2 or its ability to form heterodimers, would curtail tumor growth.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr BL-1.
Abstract BS1-1: Essential Role for Wnt Signaling in Metastatic Colonization
Authors: Huelsken J 
Published: August 2014

Abstract
Metastatic growth in distant organs is the major cause of cancer mortality. Formation of metastasis is a multi-step process with several rate-limiting steps: while dissemination of tumour cells appears to be an early and frequent event, successful initiation of metastatic growth, a process termed metastatic colonization, is rather inefficient and accomplished only by a minority of cancer cells that reach distant sites. We now identify two key mechanisms essential for the initiation of metastasis: first, a small population of cancer stem cells that are critical for metastatic colonization, i.e. the initial expansion of cancer cells at the secondary site. Second, we find stromal niche signals to be crucial for this process. This niche is required to promote Wnt signaling in infiltrating cancer stem cells and thereby this pathway plays an essential role in metastatic colonization. We suggest that interfering with this stromal support may represent a novel treatment strategy against metastatic disease.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr BS1-1.
Abstract BS3-2: Molecular Imaging of Breast Cancer: Visualizing In Vivo Breast Cancer Biology
Authors: Mankoff DA , Chodosh LA 
Published: August 2014

Abstract
The ability to measure biochemical and molecular processes underlies progress in breast cancer biology and treatment. These assays have traditionally been performed by analysis of cell culture or tissue samples. More recently, functional and molecular imaging allows in vivo assay of biochemistry and molecular biology that is highly complementary to tissue-based assay. Molecular imaging can serve and number of roles, from characterization of pre-clinical models, to testing the ability of novel drugs to interact with their intended targets, to characterizing entire burden of disease for patients with breast cancer, to helping direct therapeutic choices and assign their efficacy.
This talk will review basic principals of molecular imaging, with an emphasis on those methods of greatest translational potential. The session will discuss the use of pre-clinical models of breast disease to help test and validate new molecular imaging methods, and in turn, the use of molecular imaging to characterize the disease process in the animal models. The session will then review the current state of molecular imaging in breast cancer patients, including methods in routine clinical use, those undergoing advanced clinical trials, and those in early-phase testing.
The session is designed for a broad audience, ranging from breast cancer translational scientists to practicing physicians caring for breast cancer patients.
References
1. Vernon AE, Bakewell SJ, Chodosh LA. Deciphering the molecular basis of breast cancer metastasis with mouse models. Rev Endocr Metab Disord. 2007 Sep;8(3):199–213. 2. Mankoff DA. Molecular imaging as a tool for translating breast cancer science. Breast Cancer Res. 2008;10 Suppl 1:S3. 3. Specht JM, Mankoff DA. Advances in molecular imaging for breast cancer detection and characterization. Breast Cancer Res. 2012 Mar 16;14(2):206.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr BS3-2.
Abstract ES1-1: Molecular Profiling for In Situ Carcinoma of the Breast
Authors: Solin LJ 
Published: August 2014

Abstract
The management of in situ carcinoma of the breast represents a clinical dilemma. Such a non-invasive lesion places the patient at risk for subsequent development of an invasive lesion, and various treatments have been shown to reduce this risk. However, most patients are asymptomatic at initial presentation, and standard treatments are associated with the risk of side effects. It can be difficult for the individual patient to find the most appropriate balance between the risks and benefits of adding treatment. Although many patients elect for all treatments to minimize risk of progression regardless of potential side effects, other patients elect against treatment, often because of the potential risk of associated side effects.
Standard approaches to managing the patient with in situ disease have employed various clinical and pathologic characteristics to assess and stratify risk. Models for determining risk have used a number of clinical and pathologic characteristics, including patient age, lesion size, and grade. Ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) have different risk profiles. For example, LCIS is well known to have subsequent risk that is more frequently bilateral than DCIS.
Prospective randomized clinical trials for DCIS have demonstrated a substantial reduction in the risk of recurrence associated with adding radiation treatment and tamoxifen after lumpectomy. Five randomized DCIS trials have shown that adding radiation treatment after lumpectomy lowers the risk of local recurrence and invasive local recurrence in the ipsilateral breast by approximately 50%. Two randomized DCIS trials have demonstrated that adding tamoxifen reduces the risk of all breast cancer events (combined ipsilateral plus contralateral) by approximately 30–40%. No survival benefit has been shown for adding either radiation or tamoxifen. For LCIS, hormonal treatment has been shown to reduce subsequent risk.
More recent efforts have focused on the value of molecular markers to individualize and tailor risk profiling for the individual patient. Using such molecular risk profiling, adding treatment can be selected for higher risk patients, and omitting treatment can be chosen for lower risk patients. To be clinically useful, molecular profiling should demonstrate value beyond that seen using standard clinical and pathologic factors. While current efforts have focused on using molecular profiling as a prognostic factor, future efforts will evaluate molecular profiling as a predictive factor.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES1-1.
Abstract ES3-1: Early Phase Trials – What Are They For?
Authors: Hilsenbeck SG 
Published: August 2014

Abstract
Early in drug development, there are lots of things we need to learn about new agents or new combinations of agents in order to make ‘good’ decisions about whether and how to proceed. The landscape of clinical trials is changing, with greater focus on targeted therapies and biomarker defined patient populations. Trial design, as we will hear in this session, must adapt to these new challenges. However, fundamentals still apply. We still need to demonstrate that drugs are safe and effective. As an introduction to the session, we will review the basic steps in drug development, especially early development, and the basic questions that must be answered at each step, in order to develop evidence for safety and efficacy.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES3-1.
Abstract ES3-4: Clinical Trial Designs for New Therapies: When Should We Randomize?
Authors: Hunsberger S 
Published: August 2014

Abstract
There is a tension in clinical trial study design between the desire to keep the number of patients in a study small (so that as few patients as possible are exposed to potentially harmful agents, resources are minimized, and an answer is obtained as early as possible) and how much certainty is needed in the conclusion of the study. Different phases of drug development require different levels of certainty. Single arm studies require fewer patients than randomized studies but an observed improvement in the study defined endpoint in a single arm study may be observed for reasons unrelated to the experimental treatment. In randomized studies factors (known and unknown) that influence the endpoint of interest should be balanced between groups therefore any improvement in the endpoint of interest can be attributed to the experimental agent. In this talk I discuss circumstances that would be appropriate to perform single arms studies and circumstances that require randomized studies.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES3-4.
Abstract ES4-2: Cognitive Changes and Breast Cancer Treatments
Authors: Ganz PA 
Published: August 2014

Abstract
Cognitive difficulties after cancer treatment are among the most feared outcomes voiced by patients who are approaching the start of chemotherapy. This phenomenon, sometimes referred to as “chemo brain” or “chemo fog,” is quite common during the acute course of chemotherapy treatment. This may result from direct antieneoplastic drug toxicity, use of premedications and anxiolytics to prevent nausea and vomiting, as well as the expected anxiety, depression, and sleep deprivation that accompanies a new diagnosis of cancer and initiation of treatment. For most patients, this fog clears after the completion of acute treatments, and as with many physical symptoms, resolves in the following months. However, 15–25% of post-treatment patients, cognitive complaints persist long after treatment ends. Reports of difficulty concentrating, remembering recent events, multi-tasking, and paying attention are frequent in such patients. For those used to carrying on demanding executive function activities prior to cancer treatment, this can lead to substantial disruption in work and home life. Most of the studies conducted to date with early stage breast cancer have not accounted for the impact of adjuvant endocrine therapy alone or added to adjuvant chemotherapy. This presentation will review emerging data regarding self-reported cognitive complaints, neuropsychological testing, and brain imaging as they related to adjuvant therapies for breast cancer. In addition, some of the developing information about potential mechanisms associated with this late effect will be discussed.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES4-2.
Abstract MS3-3: Navigating the Genome: Quandaries and Approaches to Dealing with Genomic Information
Authors: Evans JP 
Published: August 2014

Abstract
Recent technological advances have made large-scale DNA sequencing, including whole genome sequencing, a practical reality. The ability to sequence tumor genomes as well as the germ-line genome of individuals holds considerable promise for the practice of oncology. Broad assessment of cancer risk in individuals, identification of those at extreme risk for cancer who might benefit from specific interventions and pharmacogenomic guidance regarding therapy are possible benefits of assessing an individual's genome. Likewise, analysis of genomic information in tumors is poised to begin helping to guide highly specific treatment of cancer in an increasingly individualized manner.
However, as the field of oncology begins to use genomic queries to assess patient risk, characterize disease and guide treatment, many challenges must be addressed. Purely technical issues include the suboptimal accuracy of current platforms for massively parallel sequencing, tumor heterogeneity and difficulties interpreting genomic risk information in a clinically relevant manner. Systemic challenges include how to interpret, store and present massive amounts of genomic data in the currently highly fragmented (and limited) electronic medical record. Finally, in the process of genome-scale sequencing vast numbers of incidental results are inevitably generated, which may have important ramifications for patients and providers but may be unwelcome. Such ethical, legal and social implications of whole genome sequencing raise significant questions about patient autonomy, the physician's duty to warn and the laboratory's duty to report a wide variety of highly heterogeneous genomic findings. In this presentation some of these salient issues and possible solutions will be explored.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr MS3-3.
Abstract OT1-1-01: A phase II study of neoadjuvant epirubicin/cyclophosphamide (EC) followed by weekly nanoparticle albumin-bound paclitaxel with or without trastuzumab for node-positive breast cancer
Authors: Hirano A , Hattori A , Kamimura M , Ogura K , Kim N , Setoguchi Y , Okubo F , Inoue H , Jibiki N , Miyamoto R , Kinoshita J , Kimura K , Fujibayashi M , Shimizu T 
Published: August 2014

Abstract
Background: Paclitaxel is considered standard treatment for metastatic breast cancer (MBC) and is often used as adjuvant and neoadjuvant chemotherapy for patients with early-stage disease. Conventional paclitaxel requires solvents such as polyoxyethylated castor oil; however, such solvents are associated with toxicity including peripheral neuropathy and hypersensitivity reaction. Moreover, the use of the drug requires special tubing and in-line filters. Therefore, nanoparticle albumin-bound paclitaxel (nab-PTX) requiring no solvent has been developed. Nab-PTX was effective in patients with MBC and as a neoadjuvant therapy. A comparison between weekly and triweekly nab-PTX suggested that weekly nab-PTX was superior in progression-free survival.
Trial design: This is a phase II trial to evaluate the efficacy and toxicity of neoadjuvant epirubicin/cyclophosphamide (EC) (epirubicin/cyclophosphamide) followed by weekly nab-PTX with or without trastuzumab for node-positive breast cancer. Patients receive four cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks, followed by four cycles of nab-PTX (125 mg/m2) on days 1, 8 and 15 in a 28-day cycle. Fifteen cycles of trastuzumab (2 mg/kg, loading 4 mg/kg) are added to the nab-PTX regimen in HER2-positive patients every week.
Eligibility criteria: Patients with histologically diagnosed invasive breast cancer based on a core needle biopsy of the T1-4 N1-3 without previous operation or chemotherapy are included in this trial. Eligible patients are aged between 20 years and 70 years with a performance status of 0 to 2 and adequate organ functions.
Specific aims: The primary endpoint is the pathologic complete response (pCR) rate in the breast and axilla, and the secondary endpoints are the breast conserving rate, toxicities, feasibility and overall survival.
Statistical methods: The sample size was calculated using the Simon method, with a type I error of 10% and a study power of 80%. 1. HER2-negative patients
The expected rate of pCR was 25% and the required number of patients was estimated to be 33. 2. HER2-positive patients
The expected rate of pCR was 50%, and the required number of patients was estimated to be 21.
Present and target accrual: Patient accrual within two medical centers started in April 2011 with 20 patients being on study to date (2012, June 12). A total of 56 patients (22 are HER2-positive and 34 are HER2-negative) are planned to be enrolled in the trial.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-01.
Abstract OT1-1-03: PERSEPHONE: Duration of Trastuzumab with Chemotherapy in women with HER2 positive early breast cancer.
Authors: Earl HM , Cameron DA , Miles D , Wardley AM , Ogburn ERM , Vallier A-L , Loi S , Higgins HB , Hiller L , Dunn JA 
Published: August 2014

Abstract
Background: Persephone is a phase III randomised controlled trial comparing six months of trastuzumab to the standard 12 month duration in patients with HER2 positive early breast cancer in respect of disease free survival, safety and cost-effectiveness. A Persephone sister study, the PHARE trial run by the National Institute for Cancer, successfully closed to recruitment in 2010. A prospective meta-analysis is planned once each trial has reported individually.
Methods: A total of 4000 patients will be randomised into each of the two treatment groups. Eligible participants must be Her2 positive with a histological diagnosis of invasive breast cancer and no evidence of metastatic disease. Patients will receive neo-adjuvant or adjuvant chemotherapy and have no previous diagnosis of malignancy unless managed by surgical treatment only and disease-free for 10 years. Patients can be randomised at any time prior to receiving their 10th cycle of trastuzumab.
The power calculations assume that the disease-free survival (DFS) of the standard treatment of 12 months trastuzumab will be 80% at 4 years. On this basis, with 5% 1-sided significance and 85% power, a trial randomising 2000 in each arm will have the ability to prove non-inferiority of the experimental arm defining non-inferiority as ‘no worse than 3%’ below the control arm 4 year DFS. Primary outcome is disease-free survival non-inferiority (equivalence) of 6 months trastuzumab compared with 12 months in women with early breast cancer. Secondary outcomes are overall survival non-inferiority (equivalence); expected incremental cost effectiveness; cardiology function and analysis of predictive factors for development of cardiac damage. Two mandatory sub-studies are: Tumour block collection to discover molecular predictors of survival with respect to duration of trastuzumab treatment and blood sample collection, used to discover single nucleotide polymorphisms (SNPs) as genetic/pharmaco-genetic determinants of prognosis, toxicity and treatment outcome. A third optional sub-study is the quality of life questionnaires.
Results: Persephone opened to recruitment in October 2007. To date, 2152 patients (54%) of its total have been randomised from 147 UK sites. Recruitment is due to complete by December 2013 and the first planned interim analysis of the primary outcome will be mid-2016.
Conclusion: The IDSMC last reviewed the trial in December 2011 and congratulated the Trial Management Group on the conduct of the trial and the quality of the data. No safety concerns were identified, and the IDSMC proposed that the trial continue to planned recruitment.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-03.
Abstract OT1-1-04: ALTERNATIVE: safety and efficacy of lapatinib (L), trastuzumab (T), or both in combination with an aromatase inhibitor (AI) for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer
Authors: Johnston S , Wroblewski S , Huang Y , Harvey C , Nagi F , Franklin N , Gradishar W 
Published: August 2014

Abstract
Background: Overexpression of the human epidermal growth factor receptor 2 (HER2) gene in breast cancer is associated with an aggressive phenotype, poor prognosis, and resistance to endocrine therapies. Of HER2+ patients, ∼50% are also hormone receptor-positive (HR+). For patients who are both HER2+ and HR+, combining the AI letrozole with the dual tyrosine kinase inhibitor L has been shown to improve outcomes compared with letrozole alone. The combination of L and T, a humanized monoclonal antibody-targeting HER2, has been shown to improve outcomes compared with L alone.
Trial design: The ALTERNATIVE study is a Phase III, randomized, open-label, multicenter trial, which will examine the efficacy of L/T/AI in combination versus T/AI alone. Patients will be randomized to 1 of 3 treatment arms: L 1000 mg po QD plus T (loading dose of 8 mg/kg followed by maintenance with 6 mg/kg IV q3w plus an AI po QD); T plus an AI; or L 1500 mg po QD plus an AI. Choices of AI include letrozole, anastrozole, or exemestane.
Eligibility criteria: Postmenopausal female patients with HER2+/HR+ metastatic breast cancer (MBC) who have received neo/adjuvant T and endocrine therapy, are treatment naïve for MBC, and are not candidates for chemotherapy.
Specific aims: The primary efficacy endpoint is overall survival (OS), defined as the time from randomization until death due to any cause, for L/T/AI compared with T/AI alone. Secondary efficacy objectives include comparisons of OS between T/AI and L/AI as well as between T/L/AI and L/AI in addition to comparisons of progression-free survival, overall response rate, time to response, and duration of response. The safety objective is to evaluate the safety and tolerability for all 3 treatment groups.
A 4-year recruitment is anticipated. More than 200 centers across 37 countries are planned; approximately 110 centers are currently open for enrollment.
Statistical methods: The study is powered to detect a 42% reduction in risk of death (hazard ratio=0.70) in patients who receive L/T/AI (median 28.5 months) versus T/AI (median 20 months) using a 1-sided test for superiority with α=0.025. The required number of total events to achieve a power of 80% is 249. Secondary comparisons are not powered and will be based on the intent-to-treat population.
Present and target accrual: Twenty-six (26) of 525 patients have been randomized. Patients who have participated in previous neo-/adjuvant trials including a T regimen are eligible, provided they meet all other inclusion criteria.
The study is currently recruiting patients, with an anticipated target accrual of 525 patients by March 2016.
Clinical trial registry number: NCT01160211
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-04.