bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD09-05: SU2C Phase Ib Study of pan-PI3K Inhibitor BKM120 Plus Aromatase Inhibitor Letrozole in ER+/HER2− Metastatic Breast Cancer (MBC).
Authors: Mayer IA , Balko JM , Kuba MG , Sanders ME , Yap J , Li Y , Winer E , Arteaga CL 
Published: June 2012

Abstract
Background: Experimental evidence and clinical data suggest that PIK3CA mutations (present in approximately 35% of ER+ cancers) are associated with de novo or acquired resistance to antiestrogen therapy. Considering that most breast cancers resistant to antiestrogen therapy retain ER and estrogen sensitivity, treatment of ER+ breast cancers with single-agent PI3K-targeted therapy may be insufficient to inhibit tumor growth.
Materials and Methods: To evaluate safety/tolerability, we initiated a phase Ib clinical trial of letrozole with the pan-PI3K inhibitor BKM120 (Novartis) in post-menopausal patients with ER+/HER2−MBC. Letrozole (2.5 mg/d) and BKM120 (100 mg/d) were given on a 28-day cycle. When necessary, BKM120 was reduced to 80 and 60 mg/day. Treatment was continued until unacceptable toxicity or progression of disease. Disease was assessed every 2 months. FDG-PET imaging was performed at 2 weeks to identify changes indicative of pharmacodynamic modulation of PI3K/AKT.
Results: Twenty patients have been accrued; all but 2 patients had previously progressed on an aromatase inhibitor (AI) in the metastatic setting. Median age was 56 years; 85% of patients had metastatic bone disease, 70%, visceral metastases. Twelve patients are still on treatment, 2 of these are currently on BKM120 80 mg/day. Three patients discontinued treatment within 2 months of initiation due to grade 3 transaminitis, grade 2 irritability, and grade 2 hyperglycemia, despite dose reductions and/or optimal treatment. Most common toxicities are summarized in the table below. Transaminase elevation was the only DLT at 100 mg/d BKM120. Of the 12 evaluable patients that completed at least 8 weeks of treatment, 1 had a partial response, 7 had stable disease, and 4 had disease progression (RECIST). So far 3 patients have been on treatment for &gt;4 months. Over 50% of patients had &gt;25% reduction in their peak SUV at the 2-week FDG-PET scan.

Discussion: The letrozole + BKM120 combination is active in patients with ER+/HER2− MBC refractory to previous therapy with an AI. At this time, all patients’ primary diagnostic tumor biopsies and/or metastatic biopsies are being analyzed for the presence of PIK3CA, AKT1, or PTEN mutations and PTEN loss (immunohistochemistry). FDG-PET imaging at 2 weeks appears to be a useful pharmacodynamic biomarker of PI3K pathway inhibition. Correlation of mutational analysis with clinical benefit will be presented at the meeting. Despite an overall safe side effect profile, an alternative administration schedule of BKM120 with letrozole is planned to enhance tolerability of the combination.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-05.
PD09-06: Phase II Trial of RAD001 (Everolimus), an mTOR Inhibitor, with Weekly Cisplatin and Paclitaxel in Patients with HER2−Negative Metastatic Breast Cancer (MBC).
Authors: Mayer IA , Means-Powell J , Abramson VG , Shyr Y , Balko JM , Kuba MG , Gharavi HM , Schlabach L , Arteaga CL , Pietenpol JA 
Published: June 2012

Abstract
Background: In basal-like breast cancers, drugs that either negatively modulate p63 and/or activate p73, such as cisplatin and paclitaxel, promote p73-dependent apoptosis. Further, the serine threonine kinase mTOR negatively regulates p73. Inhibition of mTOR with RAD001 upregulates p73, and results in p73-mediated apoptosis. Therefore, we conducted a phase II trial in patients with HER2−negative MBC to explore safety, tolerability and anti-tumor activity of the combination of paclitaxel, cisplatin and RAD001.
Materials and Methods: We initiated an open-label, phase II multi-institutional study of weekly cisplatin (25 mg/m2), paclitaxel (80 mg/m2) and daily RAD001 (5 mg), given on a 28-day cycle. Treatment was continued until unacceptable toxicity or progression of disease. All toxicities were documented using the NCICTCv.4. Disease was assessed every 2 months.
Results: A total of 55 patients were enrolled. Median age was 55 years; 62% of patients had prior chemotherapy with a median of 3 previous regimens in the metastatic setting. Sixty-three percent of patients had triple-negative disease, 81% patients had visceral disease, and 35% had bone metastases. Twenty-one patients are still on study. The most common toxicities are summarized in the table below. Neutropenia was the main cause for dose reductions, mainly after cycle 3. Only 1 patient developed febrile neutropenia. Of the 44 patients assessed for best response (RECIST) thus far, 11 had partial response, 21 stable disease, 9 disease progression, and 3 were not evaluable. Thirty eight patients have discontinued treatment so far; 30 due to disease progression, 5 due to toxicity, and 3 withdrew consent. Current median time to progression on the evaluable patients is 6 months.

Discussion: The combination of RAD001, cisplatin and paclitaxel was overall very well tolerated despite cumulative pancytopenia. Significant antitumor activity in this heavily pre-treated patient population was seen. All patients’ primary diagnostic and/or metastatic tumor biopsies are currently being analyzed for the presence of PIK3CA and AKT1 mutations, and immunohistochemical expression of p53, p63, p73, and PTEN. Microarrays are being generated to determine whether time to progression is superior in patients with basal-like breast cancers. Microarrays will be mined to identify a pretreatment profile that mirrors a low p63/high p73 gene expression signature. Correlation of mutational analysis and gene signatures with clinical benefit will be presented at the meeting
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-06.
PD10-01: Prevalence of Dysfunctional Fanconi Anemia (FA) DNA Repair Pathway in Breast Cancer.
Authors: Ramaswamy B , Srividya V , Mullins DA , Carothers S , Young G , Wenrui D , Zhao W , Lustberg M , Leon M , Weslowski R , Layman R , Mrozek E , Shapiro CL , Villalona-Calero M 
Published: June 2012

Abstract
Purpose: BRCA1/2 deficient breast tumors are highly sensitive to poly- ADP-ribose polymerase inhibitors (PARPi). The Fanconi Anemia (FA) associated gene products along with BRCA 1/2 function in a common pathway that regulates the cellular response to DNA damage, suggesting that tumors with dysfunction of any of the components of FA network would be susceptible to PARPi. Understanding the prevalence of such defects in breast tumors using reproducible methodology will help us target these tumors with novel agents and potentially improve outcomes. Hence we sought to assess the prevalence of FA pathway defect in breast tumors by the absence of nuclear FANCD2 (a pivotal protein in the FA/BRCA pathway which is monoubiquitylated in the nucleus in response to DNA damage) repair foci using a novel immunofluorescence method and correlate this with known molecular markers of breast cancer.
Methods: Using primary tumors obtained from the ongoing PARPi clinical trials (NCT01017640 and NCT01251874) and tumor bank, we evaluated 102 breast tumors for the somatic functionality of the FA pathway (FANCD2 foci formation) by the FA Triple Stain Immuno-Fluorescence (FATSI) test performed in a CLIA-certified laboratory using paraffin embedded tissues. The tissue sections are incubated with a primary antibody cocktail of rabbit polyclonal FANCD2 antibody and a monoclonal anti-Ki67 mouse antibody, followed by co-incubation with a secondary antibody (FITC conjugated to anti-rabbit IgG and Alexafluor 594 donkey anti-mouse), mounted on glass slides in a DAPI containing embedding medium and evaluated by a fluorescence microscope. Absence of nuclear FANCD2 formation in 100 proliferating tumor cells was considered positive for FA defect. Hormone receptor (HR) and Her2 status was compared between the groups using Fisher's exact test.
Results: A total of 102 primary breast tumors were analyzed for FANCD2 by FATSI test of which 62 were triple negative (TN), 37 were HR positive and 3 were Her2 positive. Of these, 29 tumors (28%) were positive for FA defect with no significant differences among the molecular subtypes (26% in TN vs 32% in HR + vs 33% in Her2+).

Conclusions: We report a novel methodology to efficiently screen archival FFPE tumors for somatic functional defect of FA DNA repair pathway and demonstrated a high prevalence (one-third) in breast tumors irrespective of molecular subtype. We are currently conducting clinical trials with PARPi including patients with tumors that test positive for FA defect to demonstrate if such tumors are sensitive to PARPi.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD10-01.
SR2-6: Genome Data for the Masses: Presentation of TCGA and IGC Breast Tumor Data.
Authors: Haussler D 
Published: June 2012

Abstract
Large-scale cancer genomics projects will sequence tens of thousands of tumors in the next few years, along with matched normal tissue samples. Among these are The Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and the International Cancer Genomics Consortium (ICGC). TCGA alone plans to analyze 500 clinically characterized samples from each of 20 different cancer types, detecting frequently mutated genes, common copy number variants, rearrangements, altered gene expression, and methylation changes. These data will provide an exceptional resource for identifying new diagnostic targets and predictors of response.
As a data analysis center and the primary sequence database for TCGA, we have built on technology developed for the UCSC Genome Browser to develop a cancer genome analysis pipeline and a cancer genomics browser (genome-cancer.ucsc.edu). These interpret cancer genomics data to aid in the identification of new targets. We reconstruct changes in tumor genomes and their expressed transcripts from tumor sequencing data (DNA, RNA, methylation) and use an approach based on factor graphs, called PARADIGM, to map multiple data types into a single coherent pathway model that includes thousands of genes and interactions for higher-level interpretation. By transforming raw genomic data to pathway activity levels, PARADIGM provides a comprehensible window into the data that can be coupled to predictors of response to improve accuracy. This paves the way to form hypotheses that clinical investigators can test in cell-line models and later explore in clinical trials.
Today's concurrent cancer genomic projects provide an exceptional opportunity to study the molecular nature of cancer on an enormous scale never before possible. A cancer genomics data repository that hosts multiple large projects and makes them accessible through a general cancer genomics browser (with effective data access control) will leverage each study and enable cross-tumor cancer research.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr SR2-6.
Abstract A6: A global sensitivity test for evaluating hypotheses with non- and weakly identifiable statistical models: An application to breast cancer outcomes
Authors: Todem David , Cao Guanqun , Yang Lijian , Fine Jason P. 
Published: June 2012

Abstract
Background and objectives: Motivated from a study on breast cancer, we consider the problem of evaluating a statistical hypothesis when some model characteristics are potentially non or weakly identifiable from observed data. Such scenarios are common in longitudinal studies for evaluating a covariate effect when dropouts may be informative. The hypothesis related to treatment effects may not be testable nonparametrically, with untestable model restrictions necessary for inference. A popular approach is to assume a finite dimensional model and to fix a minimal set of parameters, called sensitivity parameters, conditional upon which hypothesized parameters are assumed identifiable. These profile models, viewed as a functional of the secondary or sensitivity parameters, form the basis of sensitivity analysis. In the current literature, however, inference regarding significance of the covariates is ad hoc, ignoring that multiple tests are conducted and that the working model may be misspecified.
Methods and results: In this paper, we propose conservatively testing the null hypothesis of interest across the support of the sensitivity parameters using an infimum test statistic. The test must account for the facts that inferences are carried out simultaneously across the entire range of the sensitivity parameters and that the model may be misspecified under certain values of the sensitivity parameters, as might occur if a nonignorable model is fit, when, in reality, missingness is ignorable. We characterize the limiting distribution of the statistic as a functional of processes in the sensitivity parameters, which involves a careful theoretical analysis of its behavior under model misspecification. In practice, we suggest a simple yet flexible resampling procedure to implement the infimum test as well as to construct confidence bands for simultaneous pointwise tests across all values of the sensitivity parameters. The methodology's practical utility is illustrated in simulations and an analysis of quality-of-life outcomes from a longitudinal study on breast cancer. Interestingly in this example, a covariate effect on cancer outcomes is detected over a wide range of the sensitivity parameter when a Wald test that assumes identifiability fails.
Implications and next steps: The key implication of this work is that the hypothesis of interest can be conservatively evaluated across the support of the sensitivity parameters using an infimum test statistic over the space of these parameters. A key assumption of this paper is that the working model is finite dimensional although the full specification of distribution of the data is not required. The methodology should be broadly applicable to infinite dimensional models, such as survival models for censored data. This extension is the focus of current research work.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A6.
Abstract A60: Second primary breast cancer incidence rates among black and white female breast cancer survivors
Authors: Nsouli-Maktabi Hala , Henson Donald E. , Younes Naji , Young Heather A. , Cleary Sean D. 
Published: June 2012

Abstract
Background: Breast cancer incidence increases with age and exhibits a Black-to-White incidence crossover around age 45. Breast cancer survivors are at a significantly elevated risk of developing a second primary breast compared with the general population. The purpose of this study was to determine whether a similar crossover occurs in second primary breast cancer incidence in Black and White women.
Methods: The Surveillance, Epidemiology, and End Results’ Registry 9 was used to follow 415,664 White and 39,887 Black female breast cancer survivors, diagnosed at age 19 or older, for a second primary breast cancer between 1973 and 2007. Cumulative incidence curves, which account for the competing risk of death and the occurrence of second primary non-breast cancers, were generated; Pepe and Mori's test was used to test for significance.
Results: A total of 22,290 (40.7%) second primary breast cancers were observed among 450,936 women who had survived 2 months or more after an in situ or invasive breast cancer. The majority, 18,227 (81.7%) cases, occurred in women diagnosed with a first primary breast cancer at age 45 or older. Second primary breast cancer followed the incidence pattern of the first primary breast cancer in Black and White women diagnosed before age 45. It was opposite of the pattern of first primary breast cancer in Black and White women diagnosed at age 45 or later.
Despite the Black-to-White crossover of first primary breast cancer around age 45, the incidence of second primary breast cancer was higher in Blacks than in Whites.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A60.
Abstract A61: Modulation of proteasome expression in dendritic cells and melanoma cells
Authors: Robinson John L. , Mackay Amy , Pilon-Thomas Shari 
Published: June 2012

Abstract
The proteasome is a cellular subunit that degrades intracellular proteins into small pieces called peptides. Degradation of proteins into peptides occurs through one of two types of proteasomes: constitutive proteasome (cPr) and immunoproteasome (iPr), each giving rise to a unique repertoire of peptides. Most cells, including tumor cells, express the cPr, while dendritic cells (DCs), the master T cell educators of the immune system, constitutively express the iPr. Presentation of peptides processed through the iPr in DCs may activate T cells that cannot recognize peptides processed through the cPr in tumor cells, leading to a non-functional antitumor immune response. To eliminate this problem, we have investigated the use of two drugs discovered by Onyx Pharmaceuticals that selectively inhibit either the c20S of the cPr or the i20S of the iPr in tumor cells and DCs respectively. The drug ONX 0914 inhibits iPr activity. We have determined that the ONX 0914 concentration of 250nM is optimal to block iPr function and maximize DC viability. Using ONX 0914 we have demonstrated that the major histocompatibility complex I (MHC I) Kb-restricted epitope, gp-10025-33, is processed through the iPr. The drug PR-825 inhibits cPr activity. Using PR-825, we have determined that the peptide OVA257-264 is processed through the cPr. We are using these drugs to optimize DC-based vaccines in a murine model of melanoma.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A61.
Abstract A68: Familial colorectal cancer registry in Hispanics: A feasibility study
Authors: Lozada María Eugenia , Bernabe-Dones Raúl , López-Enriquez Reynold , Haile Robert , Mosquera-Fernández Rafael , Cruz-Correa Marcia R. , Díaz-Algorri Yaritza , Acosta Delma , Nuñez Cristina , Rosado Edwin , Torres-Cintrón Mariela , Figueroa-Vallés Nayda , Cardona Alberto , Lacourt-Ventura Mercedes 
Published: June 2012

Abstract
Background: In Puerto Rico (PR), colorectal cancer (CRC) represents the second most common cause of cancer in men and women. Incidence and mortality of CRC are increasing in Puerto Rican Hispanics, especially among young individuals. Screening rates for CRC are lower in Hispanic-American individuals compared to non-Hispanic patients. However, there is limited data on genetic epidemiological CRC disparities in Hispanic patients.
Objectives: (1) To prospectively identify and recruit 30 probands with a family history of CRC and 15 family-history negative. (2) To prospectively identify and recruit selected relatives from the 45 probands.
Methods: Eligible cases are Hispanic patients with incident diagnosis of CRC, ≥ 21 years old. We identified the probands and their selected family members using the Puerto Rico Central Cancer Registry from July 1, 2007 to the present. Preliminary data and recruitment: Seven hundred and fifty-one communications were sent to the physicians, three hundred and seventy-four communications were responded (374/751=49.8%). Three hundred and forty-one communications were sent to the patients, one hundred and forty-seven letters were responded (147/341=43.1%) and 16 refused. One hundred and fifty-nine participants (probands and relatives) were enrolled. One-hundred and two probands (mean age 56.9 ± 13.3 yrs., 54.9% male); 30 with and 72 without family history of CRC. At present, we collected 153 (96.2%) risk factors questionnaires, 135 (84.9%) blood samples and 60 (52.6%) blocks of tissue.
Successful implementation of logistics for identification of incident CRC through the PR Central Cancer Registry during a three-year period. We established the first Familial CRC island-wide registry in Puerto Rico through the implementation of a network of community physicians, laboratories and professional societies. We are developing a tissue and blood bank with epidemiological, nutritional, and demographic data that will assist us to understand the genetic epidemiology of CRC in Puerto Ricans.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A68.
Abstract A69: Identification of prostate cancer genes in the African American Hereditary Prostate Cancer (AAHPC) study
Authors: Ricks-Santi Luisel J. , Mason Tshela , Abbas Muneer , Dunston Georgia M. , Kolluri Supraja , Gold Bert , Im Kate , Lautenberger James , Dean Michael , Bailey-Wilson Joan , Carpten John , Ahaghotu Chiledum 
Published: June 2012

Abstract
Background: Prostate cancer (PCa) is a common malignancy and a leading cause of cancer death among African American men. The hereditary prostate cancer 1 gene (HPC1-1q24-25) was initially implicated as a PCa susceptibility locus in 1996, but was not replicated in the African American Hereditary Prostate Cancer (AAHPC) study, which recruited African American families with four or more affected family members (n=95 families). The objective of our study is to identify and confirm PCa genetic susceptibility loci in African Americans.
Methods: Short tandem repeat polymorphism (STR) scans implicated several loci, but no specific family had a logarithm of odds score higher than 1.8. We sought to refine implicated loci through single nucleotide polymorphism microarray. Therefore, we devised a prioritization scoring system where families with multiple affected and unaffected brothers within a likely onset age bracket scored the highest. After Illumina 660K microarray run, Bayesian prior likelihoods will be coupled with family based statistics to analyze the data in 6 families (n=32).
Results: Scoring criteria was effective at identifying families (n=31, 14 cases, 17 controls) most informative at identifying genes and SNPs associated PCa. A total of 51 SNPs in 13 genes were found to be associated with PCa Risk at the p&lt;0.05 level including CTBP2 (4p16), HNF1B (17cen-q21.3), and PKHD1 (6p12.2).
Conclusions: This study is a first step in identifying PCa genes that warrant further follow-up in the rest of the AAHPC families.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A69.