bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract S3-05: Patient-derived xenograft study reveals endocrine therapy resistance of ER+ breast cancer caused by distinct ESR1 gene aberrations
Authors: Shao J , Li S , Crowder RJ , Kitchens RT , Johnson SN , Goncalves R , Phommaly C , Griffith OL , Maher C , Perou CM , Mardis ER , Ellis MJ 
Published: August 2014

Abstract
Endocrine therapy resistance occurs in 50% of estrogen receptor positive (ER+) luminal breast cancers but the underlying mechanisms are poorly understood. To gain insight, we have taken advantage of whole-genome and RNA sequencing data of five late-stage hormone-resistant luminal breast tumors all of which have been successfully established as patient-derived mouse xenograft (PDX) models. Here we describe genetic alterations in ESR1-the gene coding for ERa-in three of these five tumors. They include an ESR1 point mutation (Y537S), a gene translocation causing an in-frame fusion between N-terminal ER and C-terminal Yes-associated protein 1 (YAP1), and ESR1 gene amplification. Functional characterization of the ESR1(Y537S) mutant and ESR1-YAP1 fusion in ER+ cell lines indicated that they both possess constitutive transcriptional activity and drive hormone-independent cell proliferation, mirroring the endocrine resistance of the originating tumors and the estradiol-independent growth of the PDX tumors. ESR1 (Y537S), a known gain-of-function experimental mutation in the ligand-binding domain of ER is not seen in primary breast cancer (TCGA data), suggesting it is a mutation associated with acquired resistance. Regarding the ESR1-YAP1 fusion gene, the truncated N-terminal ER fragment lacks the hormone-dependent transactivation domain (AF2) and the ligand binding domain but retains the hormone-independent transactivation domain (AF1) and therefore drives resistance to all endocrine approaches. As for ESR1 gene amplification, the tumor of origin, though resistant to aromatase inhibition, paradoxically responded to estradiol treatment, and this was recapitulated in the PDX model. Interestingly, acquired ESR1 gene amplification also occurred in long-term estrogen-deprived breast cancer MCF-7 cells which similarly regress upon estradiol exposure. Thus, ESR1 amplification may be a biomarker for paradoxical therapy with estradiol. Together, our focused study of advanced endocrine resistant luminal breast tumors revealed three distinct mutational mechanisms affecting the ESR1 gene that drive endocrine therapy resistance. Prevalence studies using RNAseq are underway to determine the frequency of somatic changes in the ESR1 gene in advanced breast cancer samples and additional ER+ PDX models. These additional data will be presented at the meeting.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S3-05.
Abstract S4-03: Exome sequencing reveals clinically actionable mutations in the pathogenesis and metastasis of triple negative breast cancer
Authors: Blackwell KL , Hamilton EP , Marcom PK , Peppercorn J , Spector N , Kimmick G , Hopkins J , Favaro J , Rocha G , Parks M , Love C , Scotland P , Dave SS 
Published: August 2014

Abstract
Triple negative breast cancer (TNBC) represents a particularly aggressive and difficult to treat form of breast cancer. No specific genetic alterations have been described as characteristic of the disease, with the exception of association with BRCA1/2, EGFR, and KRAS mutations. In this study, we sought to define clinically actionable mutations in untreated metastatic tumors as well as compare the mutational status of metastatic samples with germ-line and primary tumors using whole exome sequencing.
We prospectively enrolled 38 patients with newly diagnosed metastatic TNBC and collected matched specimens of germ-line DNA, primary tumor and metastatic tumor. Median DFI from time of initial primary diagnosis to recurrence was 18 months (IQR = 1-24 months) and 9 patients presented with de novo metastatic disease. 34/38 patients went on to receive first-line treatment with nab-paclitaxel, carboplatin, and bevacizumab and ORR/PFS/OS are available.
Sites of TNBC metastatic tissue (n = 31) included: liver (10), chest wall (13), non-regional lymph nodes (4), and lung (4). 7 patients had inadequate metastatic tumor for sequencing. We performed whole-exome sequencing for all samples using the Agilent solution-based system of exon capture, which uses RNA baits to target all protein coding genes (CCDS database), as well as ∼700 human miRNAs from miRBase (v13). In all, we generated over 10 GB of sequencing data using high throughput sequencing on the Illumina platform.
We observed striking genetic heterogeneity among the metastatic and primary tumors. There was no single driver mutation that was common to the metastatic tumors indicating the diverse genetic pathways that contribute to metastasis. Early analysis suggests that mutations in APC and MTOR occur more frequently in metastatic tumors than in primary tumors. Nonsense mutations of ER were detected in both primary and metastatic tumors but not in germ-line DNA. EGFR and HER2 mutations were not found in any of the primary or metastatic TNBC samples.
This data provides the most comprehensive genetic portrait of metastatic and primary TNBC to date, and represents a significant first step in identifying the genetic causes of the disease, drivers of recurrence, and potential therapeutic targets. Full results, including the primary versus metastatic tumor mutational analysis will be presented.
This study was funded by a Susan G. Komen Grant SAC 100001.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S4-03.
Abstract S4-07: Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: A meta-analysis of individual patient data from randomised trials
Authors: Coleman R , Gnant M , Paterson A , Powles T , von Minckwitz G , Pritchard K , Bergh J , Bliss J , Gralow J , Anderson S , Evans V , Pan H , Bradley R , Davies C , Gray R 
Published: August 2014

Abstract
Background: Disseminated tumour cells can remain dormant in the bone marrow for years prior to subsequent activation and the development of overt metastases. Bisphosphonates (BP) have profound effects on bone physiology and could potentially modify the metastatic disease process. Variable outcomes in terms of disease recurrence have been reported, with efficacy apparently influenced by menopausal status.
Methods: We sought individual patient data for meta-analysis from 41 randomised trials that compared BP to no BP (placebo or open control). Primary outcomes were time to recurrence, time to first distant recurrence and breast cancer mortality. Predefined subgroup comparisons were of type of BP (amino-/non-amino), duration and schedule of BP treatment, menopausal status, age, ER status, concomitant chemotherapy and site of distant recurrence (bone/other).
Results: Data on 17,751 women (75% of 23,573 randomised in relevant trials) have so far been received, with around 3,300 breast cancer recurrences and 2,500 deaths. Effects on breast cancer mortality, recurrence and bone metastases for 17,016 women in the locked database and for 10,540 who were postmenopausal are shown below.
No. eventsRate Ratio (SE)10 year gain2p valueAll women (n = 17,016)Breast cancer mortality2,0490.91 (0.04)1.7%0.04Breast cancer recurrence3,2840.94 (0.04)1.0%0.13Distant recurrence2,7510.92 (0.04)1.3%0.05Bone recurrence8250.79 (0.07)1.4%0.002Other distant recurrence1,9260.99 (0.05)0.1%0.8Postmenopausal women (n = 10,540)Breast cancer mortality1,1070.83 (0.06)3.1%0.004Breast cancer recurrence1,8090.86 (0.05)3.0%0.002Distant recurrence1,5030.83 (0.05)3.3%0.0007Bone recurrence4450.65 (0.08)2.9%0.00001Other distant recurrence1,0580.93 (0.06)0.7%0.26
Reductions in bone recurrence for postmenopausal women were similar irrespective of bisphosphonate type, treatment schedule, ER status, nodal involvement or use of concomitant chemotherapy. There were no improvements in bone (RR = 1.00, 2p = 0.97) or other recurrence for premenopausal women. Adjuvant bisphosphonates also reduced bone fractures (RR = 0.83, 2p = 0.009).
Conclusion: Adjuvant bisphosphonates reduce bone recurrences and improve breast cancer survival in postmenopausal but not premenopausal women.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S4-07.
Abstract A01: No Maryland county left behind: Statewide intervention may reduce geographic disparities.
Authors: Bischoff Christina M. , Kanarek Norma F. 
Published: August 2014

Abstract
Introduction: Recent Maryland cancer planning, funding and consensus building efforts and prior screening for breast and cervical cancer have successfully reduced mortality rates and racial disparities over time. Nevertheless geographical disparities among Maryland counties have not been examined.
To date assessment of racial disparities has been accomplished using the Index of Disparity. To evaluate geographic disparities and whether every county is improving regardless of its size we suggest utilization of coefficient of variation (CV), skewness and kurtosis. We investigated geographic disparities in county cancer mortality over three time periods and between Maryland and the five adjacent states.
Methods: Using data from CDC WONDER, we assessed county breast (female), colon/rectal, lung, and prostate (male) cancer mortality coefficient of variation, skewness, and kurtosis relative to a priori critical values.
Results: Maryland counties showed a coefficient of variation consistent with adjacent state counties. In both geographic areas, breast and colon/rectum coefficients of variation were statistically below 0.25. Skewness among Maryland counties was not significant in any time period or any site except prostate cancer, significantly positive (1.36, 95% confidence intervals: 0.43-2.29) only during 1994-98. Only the adjacent state counties exhibited statistically significant skewness and kurtosis for each cancer site at some time. Coefficient of variation is most often slightly smaller than the Index of Disparity due to the larger average of county rates relative to the overall rate (weighted by county).
Conclusion: With statewide funding since 1990, Maryland has eliminated geographic disparities in breast and colon/rectum cancer but continues to exhibit borderline lung/bronchus and significant prostate disparities exhibited by “large” coefficient of variation but not – skewness and kurtosis in 2004-2008. We suggest that absence of skewness and kurtosis may be a further indication of county disparities reduction.
Tracking of disparities across counties indicated whether statewide or county-specific interventions was needed and whether progress toward elimination of disparities was made. The ideal progression of geographic disparities is indicated by a resultant very small coefficient of variation; left, if any skewness; and no kurtosis. Maryland is on track to accomplish this in all four cancer mortality indicators and on target for breast and colon and rectum.
Citation Format: Christina M. Bischoff, Norma F. Kanarek. No Maryland county left behind: Statewide intervention may reduce geographic disparities. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A01.
Abstract A66: Admixture and fine mapping in African Americans identifies a susceptibility locus for prostate cancer on chromosome 7.
Authors: Ruterbusch Julie J. , Levin Albert M. , Kittles Rick , Rybicki Benjamin A. , Bock Cathryn H. 
Published: August 2014

Abstract
Background: There are well documented racial disparities in prostate cancer among African American (AA) men in the United States. AA men have a 60% higher incidence rate and over twice the mortality rate of Caucasian men. A previous admixture mapping study identified a region on chromosome 7 where excess European ancestry was associated with increased prostate cancer risk (Bock et al., 2009). Fine mapping of this region was performed to further identify prostate cancer susceptibility loci.
Methods: DNA from 420 prostate cancer cases and 244 controls from Henry Ford Hospital in Detroit, MI and Howard University in Washington, DC was genotyped using an Illumina 1M chip. After quality control exclusions, 54,105 single-nucleotide polymorphisms (SNPs) on chromosome 7 were available for this analysis. Local ancestry was estimated using the Local Ancestry in adMixed Populations (LAMP) program, with ancestral allele frequencies obtained from HapMap. Admixture linkage was confirmed using an affected-only test. Fine-mapping within the region was conducted using the MIX-score method proposed by Pasaniuc et al. (2011) to identify the SNP(s) most likely to explain the admixture linkage.
Results: The admixture linkage signal spanned from 7q31.1 (112.27Mb) to 7q34 (137.90Mb). Within this region, there were three SNPs with MIX-score p-values less than the Bonferonni corrected significance threshold. The highest level of significance was attained at SNP rs13221538 (p=1.16*10-7). This SNP is located in an intron of the Cadherin-like and PC-esterase domain-containing protein 1 (CPED1) gene. Adjusting for local ancestry, the allelic odds ratio for this SNP was 1.52 (p=1.16*10-5), and the C allele of this SNP is more prevalent in the Northern and Western European population (CEU - 82%) than in the West African population (YRI – 60%). While little is known about the function of CPED1, it is located between genes WNT16 and ING3. WNT16 is known to be involved in oncogenesis, and the WNT pathway has been implicated in b-catenin signaling and prostate cancer development.
Conclusion: Utilizing admixture linkage information, association fine mapping has narrowed the region on chromosome 7q associated with prostate cancer risk and identified potential candidate SNPs likely to explain the observed admixture.
Citation Format: Julie J. Ruterbusch, Albert M. Levin, Rick Kittles, Benjamin A. Rybicki, Cathryn H. Bock. Admixture and fine mapping in African Americans identifies a susceptibility locus for prostate cancer on chromosome 7. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A66.
Abstract B30: Selective small molecule AXL inhibitor BGB324 overcomes acquired drug resistance in non-small cell lung carcinoma models.
Authors: Wnuk-Lipinska Katarzyna , Gausdal Gro , Sandal Tone , Frink Robin , Hinz Stefan , Hellesøy Monica , Ahmed Lavina , Haugen Hallvard , Haugen Hallvard , Xiao Liang , Blø Magnus , Micklem David , Minna John , Brekken Rolf , Zhou Longen , Lorens James 
Published: August 2014

Abstract
Axl is a member of the TAM (Tyro3, Axl and Mer) family of receptor tyrosine kinases that regulate multiple cellular responses including cell survival, proliferation, and migration. Axl expression is associated with a variety of human cancers including non-small cell lung carcinoma (NSCLC), and is predictive of poor patient overall survival. Axl is induced by the epithelial-to-mesenchymal transition (EMT) gene program in cancer cells. Axl signaling is required to maintain EMT-associated features including invasiveness, metastasis, and can confer resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), as well as other chemotherapeutic agents. BGB324 is a potent, reversible and selective small molecule inhibitor of Axl that has recently entered into phase I clinical trials. We evaluated the effects of BGB324 on NSCLC cells in in vitro 3D assays and in mouse xenograft models, in combination with targeted and chemotherapeutic agents. BGB324 in combination with EGFR TKI erlotinib demonstrated a synergistic anti-proliferation effect on NCI-H1299 (mesenchymal, EGFR wild-type, erlotinib-resistant) human NSCLC cells in 3D culture. In mouse xenograft models using NCI-H1299 cells BGB324 treatment significantly enhanced the antitumor acitivity of Docetaxel. Similarly, using the mesenchymal NSCLC cell line A549 (EGFR wild-type), the combination of BGB324 with either erlotinib or anti-VEGF agent bevacizumab showed synergistic or additive anti-tumour activity. Furthermore, in HCC827 (EGFR mutant, erlotinib-sensitive) human NSCLC xenograft model, addition of BGB324 treatment strikely delayed the emergence of acquired resistance to erlotinib. Taken together, these data suggest the first-in-class selective Axl inhibitor BGB324 can overcome acquired resistance in in vivo models of NSCLC. Studies in human NSCLC patient-derived xenograft models and mechanisms of action are in progress.
Citation Format: Katarzyna Wnuk-Lipinska, Gro Gausdal, Tone Sandal, Robin Frink, Stefan Hinz, Monica Hellesøy, Lavina Ahmed, Hallvard Haugen, Hallvard Haugen, Liang Xiao, Magnus Blø, David Micklem, John Minna, Rolf Brekken, Longen Zhou, James Lorens. Selective small molecule AXL inhibitor BGB324 overcomes acquired drug resistance in non-small cell lung carcinoma models. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B30.
Drug Repurposing Identifies a Synergistic Combination Therapy with Imatinib Mesylate for Gastrointestinal Stromal Tumor
Authors: Pessetto Ziyan Y. , Ma Yan , Hirst Jeff J. , von Mehren Margaret , Weir Scott J. , Godwin Andrew K. 
Published: August 2014

Abstract
Gastrointestinal stromal tumor (GIST) is a rare and therefore often neglected disease. Introduction of the kinase inhibitor imatinib mesylate radically improved the clinical response of patients with GIST; however, its effects are often short-lived, with GISTs demonstrating a median time-to-progression of approximately two years. Although many investigational drugs, approved first for other cancers, have been subsequently evaluated for the management of GIST, few have greatly affected the overall survival of patients with advanced disease. We employed a novel, focused, drug-repurposing effort for GIST, including imatinib mesylate–resistant GIST, evaluating a large library of FDA-approved drugs regardless of current indication. As a result of the drug-repurposing screen, we identified eight FDA-approved drugs, including fludarabine phosphate (F-AMP), that showed synergy with and/or overcame resistance to imatinib mesylate. F-AMP induces DNA damage, Annexin V, and caspase-3/7 activities as the cytotoxic effects on GIST cells, including imatinib mesylate–resistant GIST cells. F-AMP and imatinib mesylate combination treatment showed greater inhibition of GIST cell proliferation when compared with imatinib mesylate and F-AMP alone. Successful in vivo experiments confirmed the combination of imatinib mesylate with F-AMP enhanced the antitumor effects compared with imatinib mesylate alone. Our results identified F-AMP as a promising, repurposed drug therapy for the treatment of GISTs, with potential to be administered in combination with imatinib mesylate or for treatment of imatinib mesylate–refractory tumors. Mol Cancer Ther; 13(10); 2276–87. ©2014 AACR.
Abstract B16: Cells containing mutations in the cohesin component, STAG2, are sensitive to PARP inhibition
Authors: Bailey Melanie L. , O'Neil Nigel J. , Pel Derek M. van , Hieter Phil 
Published: August 2014

Abstract
Synthetic lethality (SL) has been proposed as a strategy to specifically target cells harboring cancer mutations while leaving unmutated, non-cancer cells unaffected, thus minimizing drug side effects. One genetic vulnerability common to many types of cancer is chromosome instability (or CIN). CIN can lead to increased genetic mutation and aneuploidy in cancer cells thereby distinguishing them from their normal neighbors and making it a possible candidate phenotype to target by SL. Here, we focus on the multifunctional cohesin complex that is critical for accurate chromosome segregation and genome stability because it tethers sister chromatids together after DNA replication and maintains cohesion until their separation in anaphase. Although several subunits of cohesin have been shown to be mutated in tumors, recent data identifies a cohesin component, STAG2 (Stromal Antigen 2 or SA-2) as a highly mutated gene in several types of cancer including Ewing's sarcoma, melanoma and glioblastomas (GBMs). As a previous study in our lab had shown that knockdown of any one of the core cohesion subunits SMC1A, SMC3 or RAD21 can render cells sensitive to the poly ADP-ribose polymerase (PARP) inhibitor olaparib, we sought to determine if cell lines harboring cancer-specific STAG2 mutations showed similar sensitivity. Using paired GBM cell lines containing either a truncated STAG2 or wild-type STAG2 knock-in, we found that STAG2 mutation status was, indeed, associated with significantly decreased proliferation in the presence of PARP inhibition. Interestingly, olaparib treatment led to an accumulation of cells in the G2 phase of the cell cycle and an increase in DNA damage markers. Furthermore, in the presence of increasing concentrations of olaparib, a higher percentage of STAG2-mutated cells had micronuclei and fragmented nuclei compared to their wild-type STAG2 knock-in counterparts. Taken together, these data suggest that the DNA repair enzyme PARP may be a potential therapeutic SL target for tumors harboring mutations in STAG2.
Citation Format: Melanie L. Bailey, Nigel J. O'Neil, Derek M. van Pel, Phil Hieter. Cells containing mutations in the cohesin component, STAG2, are sensitive to PARP inhibition. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B16.