bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P1-02-10: Reduced serum B-cell maturation antigen levels predict poor outcome in metastatic breast cancer patients in a phase 3 randomized 2nd-line hormone therapy trial
Authors: Ali SM , Leitzel K , Li M , Udd K , Wang J , Sanchez E , Chen H , Berenson J , Lipton A 
Published: March 2017

Abstract
Background: B-cell maturation antigen (BCMA) is a member of the tumor necrosis factor receptor family and has two ligands, B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL). These ligands activate cell proliferation and inhibit apoptosis of normal and malignant B-cells including in multiple myeloma (MM) cell lines. Berenson et al have recently reported that circulating BCMA levels are elevated in B-cell malignancies and can be used to monitor disease and predict PFS and OS for patients with MM, Waldenstroms's macroglobulinemia and chronic lymphocytic leukemia (CLL). On the other hand, recent studies have shown that serum BCMA levels are very low among patients with MM in complete remission with low antibody levels and those with primary immune deficiencies specifically those with combined variable immune deficiency and X-linked agammaglobulinemia. Studies of the potential role of serum BCMA for patients with solid tumors has not been evaluated to date.
Methods: The pretreatment serum from 139 patients with hormone receptor-positive metastatic breast cancer who were enrolled in a phase 3 randomized clinical trial of second-line hormone therapy was evaluated using an ELISA for BCMA. The BCMA ELISA was from R&D Systems (Minneapolis, MN). Serum BCMA was correlated with TTP using categorical serum BCMA cutpoints.
Results: Pretreatment serum BCMA levels had a median of 55.61 ng/ml, an interquartile range of 34.20 and 78.79 ng/ml, and full range from 3.99 to 1193.26 ng/ml. In univariate analysis for TTP, reduced serum BCMA correlated with shorter TTP at the following dichotomous cutpoints: 15 ng/ml [HR=2.60, p=0.064, n=6 (4.3%) of patients below cutpoint]; 20 ng/ml [HR=2.88, p=0.005, n=10 (7.2%) of patients below cutpoint]; 25 ng/ml [HR=2.16, p=0.023, n=13 (9.4%) of patients below cutpoint]; and 30 ng/ml [HR=1.77, p=0.016, n=27 (19.4%) of patients below the cutpoint].
Conclusions: In a phase 3 randomized clinical trial of second-line hormone therapy among patients with hormone receptor-positive metastatic breast cancer, reduced pretreatment serum BCMA was associated with shorter TTP. This may be due to the association of reduced serum BCMA with immune deficiency; and, thus, lead to shorter TTP among patients with metastatic breast cancer. Evaluation of serum BCMA as a new biomarker to predict outcomes for breast cancer and other solid tumor patients deserves further study.
Citation Format: Ali SM, Leitzel K, Li M, Udd K, Wang J, Sanchez E, Chen H, Berenson J, Lipton A. Reduced serum B-cell maturation antigen levels predict poor outcome in metastatic breast cancer patients in a phase 3 randomized 2nd-line hormone therapy trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-10.
Abstract P1-03-02: Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours
Authors: Focke CM , Decker T , van Diest PJ 
Published: March 2017

Abstract
Background
Regional differences in proliferative activity are commonly seen within breast cancers, but little is known on the degree of intratumoral heterogeneity of Ki67 expression. Our aim was to study intratumoral heterogeneity of Ki67 expression in early breast cancers and its association with clinicopathological features like estrogen receptor (ER) status, grade and histological type.
Methods
The Ki67-labelling index (Ki67-LI) was assessed in hot, cold and intermediate spots of 233 invasive breast cancers by counting a total of 1020 cells, according to a protocol of the International Ki67 in Breast Cancer Working Group. Differences between the spots per tumor were further analyzed for clinicopathological subgroups defined by ER status, grade and histological type.
Results
All clinicopathological subgroups showed significant differences in Ki67-LI between hot, intermediate and cold spots (p &lt;0.001). The coefficient of variance (CV) between the spots was higher in ER positive than in ER negative cancers (72.6% vs 49.2%, p &lt;0.001), and was highest in grade 3 (96.12%), grade 1 (87.27%) and invasive lobular tumors (83.59%), and lowest in medullary (26.48%) cancers. Nested analysis of variance indicated that in both ER positive and ER negative cancers, variance in Ki67-LI within tumours contributed more to the total variance (56% for ER positive, 60% for ER negative cancers) than the variance between tumors.
Conclusion
Intratumoral heterogeneity in Ki67-LI is an ubiquitous phenomenon across various pathological subgroups of breast cancer that may impact assessment of Ki67 levels for clinical decision making, and sheds new light on recommended cut-offs.
Citation Format: Focke CM, Decker T, van Diest PJ. Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-03-02.
Abstract P1-03-05: A comprehensive molecular analysis of medullary breast carcinoma: A model of immunomodulatory triple negative breast cancer subtype
Authors: Romero P , Deniziaut G , Benhamo V , Fuhrmann L , Berger F , Bhalshankar J , Gruel N , MacGrogan G , Popova T , Manié E , Stern M-H , Stoppa-Lyonnet D , Rouzier R , Delattre O , Bieche I , Vincent-Salomon A 
Published: March 2017

Abstract
Medullary breast carcinoma (MBC) is a rare subtype of triple negative breast cancer (TNBC)with specific genomic features within the spectrum of basal-like carcinoma. The frequent association between BRCA constitutive mutation and MBC phenotype has been reported previously. In this study including 19 MBC and 36 non-MMB basal-like carcinoma (BLC), we refine the genomic and transcriptomic knowledge about this entity. Using pan genomic Affymetrix genome-wide human SNP6.0 array, we show that i/ MBC harbour more copy number alterations and losses of heterozygocity than BLC and that ii/ the high frequency of BRCAness genomic trait among MBC. Unsupervised and supervised analysis of GeneChip Uman Genome U133 Plus 2.0 Array transcriptomic generated data confirmed that MBC clearly differ from BLC in terms of gene expression level, with 92 genes overexpressed and 154 genes underexpressed in MBC over BLC. Immune response and inflammatory response are the most differentially represented pathways in MBC over BLC. Pro apoptotic gene BCLG is by far the more overexpressed gene in MBC. A validation study conducted with RT-QPCR among 526 breast tumors form all molecular subtype confirmed the specificity of BCLG overexpression in MBC, which was confirmed at protein level using immunohistochemisytry. Moreover, we show that a vast majority of MBC belong o the immunomodulatory TNBC subtype according to Lehman et al. Finally, we confirm the better prognosis of MBC toward BLC. Our observations epitomize the importance of developing DNA repair targeting drugs and immunotherapy based trials in order to improve the outcome of such a specific entity.
Citation Format: Romero P, Deniziaut G, Benhamo V, Fuhrmann L, Berger F, Bhalshankar J, Gruel N, MacGrogan G, Popova T, Manié E, Stern M-H, Stoppa-Lyonnet D, Rouzier R, Delattre O, Bieche I, Vincent-Salomon A. A comprehensive molecular analysis of medullary breast carcinoma: A model of immunomodulatory triple negative breast cancer subtype [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-03-05.
Abstract P1-03-12: A simulation study depicting the inconsistency of adjuvant online compared to genomic testing when determining the benefit of chemotherapy
Authors: Khawaja S , Thomas D , Udayasankar S , Munir A , Huws A , Sharaiha Y , Holt S 
Published: March 2017

Abstract
Background: Prognostic factors have been used for years to determine the benefit of adjuvant chemotherapy in breast cancer. However, reporting of the size and grade of the tumor are affected by interobserver variability in reporting. This can result in a change in the results of adjuvant online and an impact on decision making of chemotherapy. On the contrary, genomic testing such as oncotype Dx is reproducible. The purpose of our study was to assess the effect of pathological discordance on the adjuvant online results on a cohort of patients who also underwent oncotype Dx testing.
Materials and Methods: A total of 143 patients' histologies were included in this study. The results of the Phase III WSG-Plan B trial concerning central vs. local grade discrepancy rates were utilized to randomly change the grade of the tumors. 61 percent of grade 1 cancers were upgraded to grade 2 and 2% upgraded to grade 3. 4 percent of grade 2 cancers were downgraded to grade 1 and 26% were upgraded to grade 3. 1 percent of grade 3 cancers were downgraded to grade 1 and 25% were downgraded to grade 2. Likewise, change was made in the size of the tumor in 20 percent of patients. 8 to 10mm, 18-20, 28-30, and 48-50mm changed to 11, 21, 31 and 51mm respectively. 11-13mm, 21-23, 31-33, and 51-53mm was changed to 10, 20, 30, and 50mm. Ten percent of patients had the ER and Her 2 status changed.
Results: The simulation results showed that when the grade was only altered, the spearman correlation of the predicted 10 year mortality on adjuvant online with the original data was significantly changed from 1 to a result of 0.788. When the changed size was additionally added, the coefficient was 0.836. With the altered ER status, the result was 0.749 and with the Her 2 change, the spearman correlation was minimally changed to 0.742. The scattergrams showed a large number of outliers when the alteration in size was added to the altered grade.
Conclusion: Our simulation study confirms that with minimal changes in the clinical parameters because of the lack of perfect correlation between pathologist's results, there is a significant difference in the 10 year predicted mortality on adjuvant online. This is one step further in understanding the lack of correlation between adjuvant online and oncotype Dx, and the inconsistency of chemotherapy decision making with the sole use of adjuvant online.
Citation Format: Khawaja S, Thomas D, Udayasankar S, Munir A, Huws A, Sharaiha Y, Holt S. A simulation study depicting the inconsistency of adjuvant online compared to genomic testing when determining the benefit of chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-03-12.
Abstract P1-04-03: Cross-talk between RNA methyltransferase and demethylase regulates breast cancer growth and progression
Authors: Subbarayalu P , Eedunuri VK , Timilsina S , Rajamanickam S , Viswanadhapalli S , Abdelfattah N , Onyeagucha BC , Cui X , Mohammad TA , Huang TH-M , Huang Y , Chen Y , Rao MK 
Published: March 2017

Abstract
The importance of RNA methylation in biological processes has just begun to emerge. However, our understanding of the role and mechanism by which RNA methylation may play a role in tumorigenesis is unclear. Here, we report that RNA N6-adenosine methyltransferase protein METTL14 supports breast cancer growth and progression. We show that METTL14 mediates its pro-tumorigenic function by activating the expression of RNA binding protein HuR and consequently inducing the transcriptional stability of key cell cycle-associated genes, TGFβ and its signaling partners as well as HMGA2, VEGF and PDGF that are known to play critical roles in cancer growth and metastasis. Importantly, m6 A RNA methylation levels of METTL14 target genes were significantly lower in breast cancer patients compared to normal matched controls. The decreased RNA methylation level resulting in increased activity of these target genes in breast cancer patients is regulated by a feedback loop between RNA demethylase ALKBH5 and METTL14. Our results reveal that ALKBH5 regulates the expression of METTL14 and HuR, which in turn transcriptionally stabilizes ALKBH5. Furthermore, we demonstrate that like METTL14, ALKBH5 also supports breast cancer growth and progression. Taken together, these findings suggest that a collaboration between RNA methylation and demethylation machinery may set up a threshold of RNA methylation that ensures the stability of genes that play a vital role in normal cell proliferation; and any perturbation of that threshold may lead to uncontrolled expression/activity of those genes resulting in tumor growth and progression.
Citation Format: Subbarayalu P, Eedunuri VK, Timilsina S, Rajamanickam S, Viswanadhapalli S, Abdelfattah N, Onyeagucha BC, Cui X, Mohammad TA, Huang TH-M, Huang Y, Chen Y, Rao MK. Cross-talk between RNA methyltransferase and demethylase regulates breast cancer growth and progression [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-04-03.
Abstract P1-04-07: Environmental influence on epigenetic markers in the development of breast cancer
Authors: He C , Wu W , Gao H , Nephew K , Li L , Schneider B , Han J , Liu Y 
Published: March 2017

Abstract
Aberrant DNA methylation plays an important role in breast cancer initiation and progression. We hypothesize that environmental risk factors contribute to causal alterations in DNA methylation and that such causal changes have already occurred prospectively in normal breast tissue before tumor occurrence. In order to test this hypothesis, normal breast tissue from healthy women must be used. We therefore conducted an integrative molecular epidemiological study that combined the environmental regulation of DNA methylation in normal breast tissue and the differential DNA methylation profiling in tumor and normal breast tissue. We examined for the first time the environmental impact on DNA methylation in normal breast tissue from healthy women and determine the association of these epigenetic changes with breast cancer development. Potentially causal DNA methylation markers identified from our study has the potential to make a major scientific and clinical impact in understanding breast cancer etiology as well as developing novel, more effective prevention and treatment strategies.
Citation Format: He C, Wu W, Gao H, Nephew K, Li L, Schneider B, Han J, Liu Y. Environmental influence on epigenetic markers in the development of breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-04-07.
Abstract P1-05-14: Copy number aberration-induced gene breakage analysis identifies recurrent FOXP1 fusions in breast cancer
Authors: Mohd Noor A , Maguire S , Watkins J , Quist J , Mirza H , Tutt A , Gillett C , Natrajan R , Grigoriadis A 
Published: March 2017

Abstract
Background: Genomic instability is a critical feature of breast cancers, which manifests in genome-wide copy number aberrations (CNA), often causing “gene breakage” and the generation of fusion genes. We aimed to identify aborted transcripts with underlying CNAs and to investigate the molecular landscape of breast cancers harbouring such events.
Methods: A walking student's t-test algorithm was applied to Affymetrix Exon 1.0ST array data of 123 breast cancers to identify regions of aborted transcription and overlaid with DNA breakpoints derived from matched Affymetrix SNP6 ASCAT-segmented copy number. Aborted transcripts were investigated as potential fusion gene partners through RNA-seq analysis of 151 breast cancer samples (TCGA) and 51 breast cancer cell lines (BCCL) using ChimeraScan. Clinical correlates were established for clinicopathological features, genomic instability measures, and gene expression-based molecular classifiers including PAM50, TNBCtype, IntClust subtypes and immune signatures.
Results: One hundred and six genes with recurrent CNA-induced aborted transcription were identified. Aborted transcription showed hormone receptor subtype-specificity for 7 genes (nTNBC=1, nNon-TNBC=6) and was less prevalent in samples of IntClust 2 and IntClust 4 subtypes (p: 0.0043, 0.0011). Aborted transcripts were more frequently observed in samples with greater copy-neutral loss of heterozygosity (p=0.012), while aborted transcription of 54/106 genes significantly affected enrichment of 27 tumor-infiltrating lymphocyte subpopulations.14 aborted transcripts were found as a fusion gene with one partner in RNA-seq of TCGA and BCCL, while 19 were involved in multiple fusion events (range=1-6, median=2). Nine of 106 genes displayed gene breakage and fusion events exclusively in samples with an enriched tandem duplication phenotype. Notably, FOXP1, localised to a tumour suppressor locus at 3p14.1, reported the highest number of fusion configurations (n=6) with concurrent aborted transcription across all RNA-seq datasets (nPRADA=9, nTCGA=38, nBCCL=6).
Conclusion: CNA-induced gene breakage affects the molecular landscape of breast cancers and is linked with many genomic configurations of interest including copy-neutral loss of heterozygosity and tandem duplications. In particular, the role of recurrent gene fusions of the tumour suppressor, FOXP1, in tumourigenesis warrants further investigation.
Citation Format: Mohd Noor A, Maguire S, Watkins J, Quist J, Mirza H, Tutt A, Gillett C, Natrajan R, Grigoriadis A. Copy number aberration-induced gene breakage analysis identifies recurrent FOXP1 fusions in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-14.
Abstract P1-05-17: Interrogating the impact of pregnancy on breast cancer biology using DNA copy number profiling
Authors: Nguyen B , Brown DN , Rothé F , Desmedt C , Majjaj S , Pruneri G , Peccatori F , Azim HA , Sotiriou C 
Published: March 2017

Abstract
Background
Epidemiological evidence indicates a clear relationship between pregnancy and breast cancer (BC) risk. However, little is known regarding the impact of pregnancy on BC biology. DNA copy number aberrations (CNAs) play an important role in breast carcinogenesis. BC during pregnancy is a rare disease but yet could serve as a good model to study the impact of pregnancy on BC biology.
Methods
We retrospectively included 54 pregnant and 113 non-pregnant BC patients matched for age and stage with complete clinico-pathological, gene expression and 5-year follow-up data. CNAs were assessed using Affymetrix OncoScan FFPE arrays. We identified the CNAs associated with pregnancy using a multivariate logistic regression adjusted for classical clinico-pathological features. We further evaluated their impact on gene expression.
Results
After quality control, CNA profiles were obtained for 38 pregnant and 87 non-pregnant BC patients. We identified 13 regions with copy number gains, 11 of which were more frequently gained in pregnant compared to non-pregnant controls and 5 regions with copy number loss, 3 of which were more frequently lost in pregnant patients (p≤0.05). Of interest, we identified 4 genes previously identified as driver event associated with CNAs in breast cancer (S. Nik-Zainal et al, Nature 2016). AKT1 and CDKN2A/B were more frequently gained in the pregnant compared to the non-pregnant (23.7% vs. 8.0%, p=0.068 and 18.4% vs. 4.6% p=0.036) and ARID1B was less frequently gained in the pregnant cohort (2.6% vs. 13.8%, p=0.02). Interestingly, PAPPA which had been previously identified as a pregnancy-dependent oncogene (Takabatake Y. et al, EMBO Mol Med. 2016) was also more frequently gained in the pregnant compared to the non-pregnant patients (21.1% vs 5.8%, p=0.03). We next evaluated the effect of these CNAs on their own gene expression levels and found that AKT1 and CDKN2A/B CNAs were affected by gene-dosage effect.
Conclusions
In this study, we were able to identify several genomic alterations associated with pregnancy that could further elucidate the impact of pregnancy on BC risk. Moreover, by combining CNAs with gene expression, we were able to identify genes whose expression were associated with CNAs and therefore could be considered potential drivers of this rare disease.
Citation Format: Nguyen B, Brown DN, Rothé F, Desmedt C, Majjaj S, Pruneri G, Peccatori F, Azim Jr HA, Sotiriou C. Interrogating the impact of pregnancy on breast cancer biology using DNA copy number profiling [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-17.
Abstract P1-08-02: Mutant GATA3 actively promotes the growth of normal and malignant mammary cells
Authors: Kenny PA , Chandiramani N , Lofgren KA 
Published: March 2017

Abstract
GATA3 is a transcription factor expressed in luminal breast epithelial cells and is required for mammary gland development. Analysis of TCGA data reveals that somatic heterozygous mutations in GATA3 occur in up to 15% of estrogen receptor positive breast tumors, and that these tumors are diagnosed a median of eight years earlier than other estrogen receptor positive tumors, suggesting a more aggressive phenotype. These mutants have been proposed to be null alleles resulting in haploinsufficiency, however the mutation spectrum of GATA3 in breast cancer is in sharp contrast to that found in HDR syndrome, a true GATA3 haploinsufficiency disease. Based on this disparity, we propose that there is a selective pressure to mutate and retain a portion of the GATA3 in breast cancer. Here we focus on the GATA3 mutants which lack the second zinc finger which is responsible for GATA motif binding. Expression of these mutants accelerated xenograft tumor growth by ZR751 cells, and transgenic expression in mouse mammary glands promoted precocious lobuloalveolar development. We have used integrated gene expression and ChIP-Seq profiling to demonstrate that these zinc-finger deleted proteins retain the ability to associate with the genome by tethering to complexes associated with FOXA1 and AP-2gamma recognition motifs, where they modulate the expression of adjacent genes. These data support a model in which the GATA3 mutations recently observed in breast cancer encode for active transcription factors which elicit proliferative phenotypes in normal mammary epithelium and promote the growth of estrogen receptor positive breast cancer cell lines.
Citation Format: Kenny PA, Chandiramani N, Lofgren KA. Mutant GATA3 actively promotes the growth of normal and malignant mammary cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-08-02.