bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-02-08: Modulation of indoleamine 2, 3-dioxygenase (IDO1) expression in breast cancer cells by activated CD8+ T cells is controlled by DNA promoter methylation
Authors: Gu F , Noonepalle SK , Lee E-J , Choi J-H , Shull AY , Pei L , Sreekumar A , Ambs S , Shi H 
Published: March 2017

Abstract
Tumor infiltrating lymphocytes (TILs) play a critical role in regulating the immunomodulatory properties of triple negative breast cancer (TNBC). However, the specific adaptations that TNBC tumors undergo when challenged by lymphocyte infiltration remain unclear. In order to address this gap in knowledge, we conducted an immuno-phenotype comparison using mRNA sequencing between the TNBC cell line MDA-MB-231 and the luminal breast cancer cell line MCF7 after both were co-cultured with activated human T-cells. Although the cytokine-induced immune signature of the two cell lines were similar, MDA-MD-231 cells were able to transcribe the tryptophan catabolizing enzyme IDO1 at a significantly higher level than MCF7 cells. Stimulation with IFNg was able to differentially induce IDO protein expression and enzymatic activity in ER- cell lines compared to ER+ cell lines, though no differences were observed in upstream JAK/STAT1 signaling or IDO1 mRNA stability between the two cell lines. Further experiments showed that treatment with the demethylating agent 5-aza-deoxycytidine was able to reverse suppression of IDO1 expression in MCF7 cells, suggesting that DNA methylation serves as a potential determinant in IDO1 induction. Analysis of TCGA and other previously published breast cancer datasets revealed subtype-specific mRNA and promoter methylation differences in IDO1, with TNBC/basal-like subtypes exhibiting lower promoter methylation and higher mRNA expression than ER+/luminal subtypes. Bisulfite pyrosequencing validated the subtype-specific association of decreased promoter methylation with increased IDO1 expression in breast cancer cell lines and an independent cohort of primary breast tumors. In addition, decreased IDO1 promoter methylation and elevated IDO1 expression in basal-like breast tumors was found to be associated with increased levels of kynurenine, the metabolic product of IDO1, as well as higher numbers of CD8+ TILs. Furthermore, high kynurenine levels in breast tumors were associated with worse patient survival. Taken together, these findings suggest that subtype-specific IDO1 promoter methylation regulates the ability of breast tumors to escape from antitumor immune responses driven by CD8+ TILs and could be used as a predictive biomarker for IDO inhibitor-based immunotherapy.
Citation Format: Gu F, Noonepalle SK, Lee E-J, Choi J-H, Shull AY, Pei L, Sreekumar A, Ambs S, Shi H. Modulation of indoleamine 2, 3-dioxygenase (IDO1) expression in breast cancer cells by activated CD8+ T cells is controlled by DNA promoter methylation [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 P6-02-08.
Abstract P6-07-07: ESR1 amplification and 5'-3' exon imbalance in metastatic breast cancer
Authors: Oesterreich S , Basudan A , Preideigkeit N , Hartmaier RJ , Bahreini A , Gyanchandani R , Leone JP , Lucas PC , Hamilton RL , Brufsky AM , Lee AV 
Published: March 2017

Abstract
BACKGROUND: Growing evidence indicates that base pair mutations in ESR1 are relatively uncommon in newly diagnosed, treatment-naive breast cancer, but frequently acquired in hormone-resistant metastatic breast cancer (MBC). We and others have recently identified ESR1 gene fusion and amplification in MBC, with the ESR1 fusions generally encompassing AF1 and the DNA binding domain. The genomic break required for gene fusions often results in an imbalance in the DNA copy number of exons around the break. We examined ESR1 amplification and 5' and 3' exon copy number imbalance in MBC.
MATERIALS and METHODS: We designed NanoString DNA hybridization probes against coding and non-coding exons (n=9) in ESR1 and 15 reference probes. We analyzed 128 samples consisting of 61 ER-positive and 44 ER-negative metastases, and 23 primary breast cancers. DNA copy number (CN) was determined using nSolver, with &gt;2.7CN as copy number gain, and &gt;10 as CN amplification. ESR1 CN was calculated by averaging the DNA copy number obtained from all coding exons. The 5'-3' copy number ratio was the average copy number of the 5' exons (3-6) divided by the 3' exons (7-10).
RESULTS: 8 (13%) ER positive metastatic breast cancers showed ESR1 amplification with 5 (8%) having &gt;2.7CN, and 3 (5%) with &gt;10CN. In contrast, in ER-negative metastases, we did not detect any samples with amplification &gt;10CN, and a gain (&gt;2.7 CN) in one case. Similarly, in ER+ primary cancers we did not detect any samples with &gt;10 CN amplifications and 2 samples with CN gain (&gt;2.7 CN). ESR1 showed 5'-3' CN imbalance in 1 primary (5%) and in 5 metastatic (5%) breast cancers. We are currently confirming and expanding these data in a larger dataset.
CONCLUSIONS: In addition to ESR1 mutations, ESR1 CN amplifications and 5'-3' imbalance are represent frequent occurrences in endocrine resistant breast cancer. Future studies are aimed at understanding whether the observed exon imbalances are associated with generation of fusion proteins, and whether and how ESR1 amplifications cause changes in endocrine treatment response.
Citation Format: Oesterreich S, Basudan A, Preideigkeit N, Hartmaier RJ, Bahreini A, Gyanchandani R, Leone JP, Lucas PC, Hamilton RL, Brufsky AM, Lee AV. ESR1 amplification and 5'-3' exon imbalance in metastatic 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 P6-07-07.
Abstract P6-09-46: A comprehensive analysis of GNAS DNA copy number, levels of mRNA and protein expression in primary breast cancer
Authors: Tomiguchi M , Yamamoto Y , Yamamoto-Ibusuki M , Goto-Yamaguchi L , Fujiki Y , Sueta A , Takeshita T , Iwase H 
Published: March 2017

Abstract
Background: Result of recent advances in genetics, guanine nucleotide binding protein, alpha stimulating (GNAS), transducer of signals from G-protein coupled receptors, has been noted that this factor is related with the onset and progression of tumor in various cancers. We aimed to analyze gene amplification, mRNA and protein expression of GNAS and their potential association with clinicopathological factors and prognosis in primary breast cancer.
Methods: The cohort of this study included 432 primary invasive breast cancer patients treated with standard care at Kumamoto University Hospital between June 2000 and January 2011. We performed a comprehensive analysis of GNAS at the levels of gene copy number, mRNA and GNAS protein expression analyzed by qPCR, qRT-PCR and immunohistochemistry (IHC), respectively. In the IHC assessment of GNAS protein expression, an H-score&lt;150 was observed in 191 patients (44.2%), who were defined as having a low protein expression level, and an H-score≥150 was observed in 241 patients (55.8%) who were defined as having a high protein expression level.
Results: The median age at diagnosis was 60 (range 27-93). Three hundred fifteen (72.9%) of these were postmenopausal women. One hundred forty two patients (32.9%) had axillary lymph node metastasis. The median Ki67 labeling index was 23.6 (range 0.5-97.0). The subtypes were 321 ER+/HER2-, 24 ER+/HER2+, 34 ER-/HER2+ and 53 ER-/HER2-. Three hundred twenty one patients (75.9%) were treated with endocrine therapy and 146 patients (34.6%) chemotherapy. Most notably, a low levels of GNAS protein expression was observed in 191(44.2%) patients, and was positivity associated with Ki67 (P=0.028). Furthermore, univariate and multivariate analysis revealed that low GNAS protein expression was significantly related with poor relapse-free survival rate (Log-rank test; P=0.0013, OR:0.40, 05%CI:0.22-0.70) and breast cancer specific survival rate (Log-rank-test; P=0.041, OR:0.43, 95%CI:0.19-0.97). GNAS amplification and mRNA expression were not correlated with prognoses.
Conclusion: Contrary to expectations, GNAS expression was positively related with favorable tumor characteristics. Expression levels of GNAS protein may be an independent prognostic factor for primary breast cancer.
Citation Format: Tomiguchi M, Yamamoto Y, Yamamoto-Ibusuki M, Goto-Yamaguchi L, Fujiki Y, Sueta A, Takeshita T, Iwase H. A comprehensive analysis of GNAS DNA copy number, levels of mRNA and protein expression in primary 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 P6-09-46.
Abstract P6-09-49: Three-gene signature predictive of high residual risk of recurrence after adjuvant chemotherapy in ER-positive HER2-negative breast cancer
Authors: Györffy B , Ocana A , Herman P , Hatzis C , Pandiella A , Pusztai L 
Published: March 2017

Abstract
Background: A proportion of ER-positive, HER2-negative patients treated with both adjuvant endocrine and chemotherapy continue to remain high risk for recurrence. These individuals are the ideal patient population for future adjuvant trials.
Methods: We used gene expression data from ER+/HER2- patients who received adjuvant endocrine and chemotherapy. We utilized a training cohort of multiple gene expression datasets (N=131; GSE16391, GSE21653, GSE17907, GSE19615, GSE16716, GSE45255) and a validation cohort (N=277; GSE25066) from similarly treated ER+ patients. All data sets were generated with Affymetrix HGU133 arrays. Cox proportional hazards regression was performed across all genes using all possible cutoff values between the lower and upper quartile. Genes were ranked according to the estimated hazard rates for relapse. The top three genes were combined into a final signature that used the mean expression of these genes as the predictive score. Statistical analyses were performed in the R environment.
Results: The final signature capable to predict survival consisted of three genes, MX1, MBD4, and ZWINT. Each of these genes achieved high significance in a univariate analysis: MX1 HR=5.7 (p=1.8E-04) and HR=4.7 (p=1.3E-03), MBD4 HR=3.4 (p=2.8E-04) and HR=4.3 (p=4.4E-04), and ZWINT HR=4.4 (p=1E-03) and HR=3.7 (p=8.5E-03) in the training and validation cohorts, respectively. Using the mean expression of the three genes, the estimated hazard rates for survival were 20.5 (p=2.5E-05) and 17.5 (p=1E-04) in the two cohorts, respectively. Only one patient relapsed in each cohort. In a multivariate analysis including grade and lymph node status as covariates (size was not available), the three-gene signature retained significance (HR=13.2, p=0.011; and HR=13.9, p=0.01 in the two cohorts, respectively), while only lymph node status (HR=3.6, p=0.007) was significant in the validation cohort and no clinical variable was significant in the training cohort.
Conclusions: High expression of a 3-gene signature can identify ER+ patients who remain at very high risk for recurrence despite current adjuvant endocrine and chemotherapy.
Citation Format: Györffy B, Ocana A, Herman P, Hatzis C, Pandiella A, Pusztai L. Three-gene signature predictive of high residual risk of recurrence after adjuvant chemotherapy in ER-positive HER2-negative 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 P6-09-49.
Abstract P6-09-51: The REQUITE-AB study: Validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality of life in breast cancer patients
Authors: Rattay T , Johnson K , Azria D , Chang-Claude J , Davidson S , Dunning A , de Ruyscher D , Guiterrez-Enriquez S , Lambin P , Rancati T , Rosenstein B , Seibold P , Symonds RP , Thierens H , Valdagni R , Vega A , Webb A , Wenz F , West C , Talbot C 
Published: March 2017

Abstract
Clinically significant side-effects from radiotherapy affect around a quarter of breast cancer patients and may impact considerably on outcomes from treatment. An increasing number of replicated genetic associations for radiotherapy toxicity are being reported[1],[2]. The international REQUITE consortium aims to validate genetic markers and clinical factors implicated in radiotoxicity. The purpose of the REQUITE-AB project is to develop an integrated set of predictors for acute radiotherapy side-effects in breast cancer patients to be used as a clinical decision-making tool.
As part of the REQUITE prospective cohort study, 2,000 patients eligible for adjuvant breast radiotherapy will be recruited in nine centres across Europe and North America between April 2014 and August 2016, with centralised data management, biobanking and two years' follow-up using a standardised data collection protocol. Patient characteristics and treatment details being captured also include dose-volume histograms and DICOM files. Genotyping will take place in fall 2016. Primary endpoints are acute skin toxicity (CTC-AE v4.0) and quality-of-life (QoL) on completion of radiotherapy and at 3 months from start of radiotherapy. Secondary endpoints are late side-effects including change in breast appearance.
1,766 breast cancer patients have been recruited to date with standardized documentation of toxicity and QoL. Among patients who completed radiotherapy so far, 21.6% of patients developed grade 2 skin toxicity (brisk erythema) and 1.3% grade 3 (moist desquamation). The ability of patient, treatment and genetic variables to predict clinical outcomes and QoL will be examined.
The REQUITE study includes the largest radiogenomics cohort of breast cancer patients to date recruited under a single standardised protocol. Findings of the REQUITE-AB project are likely to inform the development of interventional biomarker trials and personalise breast cancer care in the future.
[1] Talbot et al, Br J Cancer, 2012; 107: 748-53.
[2] Seibold et al, Int J Radiat Oncol Biol Phys, 2015; 92: 1084-92.
Citation Format: Rattay T, Johnson K, Azria D, Chang-Claude J, Davidson S, Dunning A, de Ruyscher D, Guiterrez-Enriquez S, Lambin P, Rancati T, Rosenstein B, Seibold P, Symonds RP, Thierens H, Valdagni R, Vega A, Webb A, Wenz F, West C, Talbot C. The REQUITE-AB study: Validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality of life in breast cancer patients [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 P6-09-51.
Abstract P6-09-52: Prognostic factors in breast cancer (BC) associated with the development of brain metastases (BM): A retrospective study of 726 pts
Authors: Santa Cruz O , Tsoutsou P , Anchisi S , Khanfir K , Negretti L , Girardet C , Ozsoy O , Ozsahin M 
Published: March 2017

Abstract
This abstract was not presented at the symposium.
Abstract P6-09-54: Long-term recurrence risk and risk-based follow-up after breast cancer treatment
Authors: Siesling S , Witteveen A , de Munck L , Groothuis-Oudshoorn K , Sonke G , Klaase J , Boersma L , Poortmans P , IJzerman M 
Published: March 2017

Abstract
This abstract was not presented at the symposium.
Abstract P6-11-16: PYTHIA: A phase II study of palbociclib plus fulvestrant versus placebo plus fulvestrant for pretreated patients with ER+/HER2- metastatic breast cancer
Authors: Zardavas D , Regan M , Maibach R , Ruepp B , Hiltbrunner A , Blacher L , Goulioti T , Gelber R , Flamen P , Piccart M , Malorni L 
Published: March 2017

Abstract
This abstract was not presented at the symposium.
Abstract P6-17-01: Adjuvant treatment with zoledronic acid (ZOL) in stage II/III breast cancer. The AZURE trial (BIG 01/04) 10 year follow-up
Authors: Coleman R , Collinson M , Bell R , Marshall H , Dodwell D , Keane M , Gil M , Gregory W , Cameron D 
Published: March 2017

Abstract
This abstract was not presented at the symposium.
Abstract PD8-03: Differences in the mutational landscape in African Americans and Caucasians with triple negative breast cancer
Authors: Ademuyiwa FO , Tao Y , Luo J 
Published: March 2017

Abstract
Background-Triple negative breast cancer (TNBC) occurs at a higher frequency in African American (AA) premenopausal women compared with Caucasians. It is unclear if the biology and clinical outcome of TNBC is different in AA versus Caucasians. In this study, we sought to evaluate differences in the molecular pathology of TNBC in a large cohort of AA and Caucasians.
Methods-Using publicly available data from The Cancer Genome Atlas, we identified all patients with TNBC who had information on race. We analyzed the differences in clinical characteristics and tumor somatic mutations by race from whole exome sequencing using student's t test or one-way ANOVA for continuous variables and chi square or Fisher's test for categorical variables. Exome sequencing was performed with coverage of ≥70% and at a depth of 20x.
Results-A total of 1104 primary breast cancer patients were identified, of which 178 (16%) had TNBC. Overall, TNBC was more frequent in AA than in Caucasians (33.3% versus 14.9%; p value &lt;0.001). More AA than Caucasians were classified as basal-like from PAM50 gene expression analysis (34.8% versus 16.1%; p value 0.001). No differences in the TNBC cohort were observed, 91% of AA were basal-like versus 81% of Caucasians (p value 0.842). Median tumor somatic mutation counts were higher in AA (39.5) versus Caucasians (34) (p value 0.022). However, no racial differences in the mutation counts in TNBC were observed (AA=56, Caucasians=60, p value 0.399). Somatic mutation analysis revealed racial differences in specific high prevalence (&gt;5%) genes in all patients- [TP53 alterations: 46% in AA versus 27% in Caucasians; p value &lt;0.001, PIK3CA alterations: 23% in AA versus 34% in Caucasians; p value 0.019, and MLL3 alterations: 12% in AA versus 6% in Caucasians; p value 0.028]. The TNBC patients did not have any specific high prevalence (&gt;5%) genes associated with racial differences. AA with breast cancer had a shorter time to progression (TTP) (hazard ratio 1.62, p value 0.014) and worse disease free survival (DFS) than Caucasians. However, racial difference in TTP or DFS were not observed in the TNBC patients.
Conclusion-The mutational landscape of breast cancer may be different between AA and Caucasians, but appears to be similar in both races in the cohort with TNBC. Our findings have 2 implications: racial disparities in breast cancer may largely be due to differences in those with hormone receptor positive disease, and secondly, the higher frequency of TNBC in AA is unlikely due to differences in molecular features, but other modifiable factors.
Citation Format: Ademuyiwa FO, Tao Y, Luo J. Differences in the mutational landscape in African Americans and Caucasians with triple negative 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 PD8-03.
Abstract A27: Addiction to the NF-κB–triggered IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells
Authors: Tominaga Kana , Gotoh Noriko 
Published: March 2017

Abstract
An inflammatory microenvironment contributes to tumorigenesis. The pro-inflammatory transcription factor nuclear factor-kappa B (NF-kappa B) is known to play important roles, but how it regulates cancer stem cells (CSCs) remains largely unclear. We comprehensively analyzed which targets of NF-kappa B are activated by heregulin (HRG), a tumor sphere-forming ligand, in breast cancer cells. We identified many cytokines downstream of HRG-phosphatidyl inositol 3 kinase (PI3K)-NF-kappa B signaling. Insulin-like growth factor 2 (IGF2) was identified as a key downstream target; IGF2 treatment induced tumor spheres in most samples of patient-derived primary breast cancer cells, and anti-IGF2 antibody treatment greatly reduced HRG-induced tumor sphere formation, even though many other cytokines were simultaneously produced. The IGF2 receptor, IGF-1R, was specifically expressed at high levels in CSC-enriched populations in freshly obtained primary breast cancer cells. Moreover, IGF2-PI3K signaling induced expression of a stemness transcription factor, ID1, and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft (PDX) model. Thus, NF-kappa B may trigger IGF2-ID1-IGF2 positive feedback circuits and PI3K-mediated feed-forward circuits that allow cancer stem-like cells to appear; it may then stabilize the feedback circuits, to which the cancer stem-like cells become addicted. Because the stemness circuits may be the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.
Citation Format: Kana Tominaga, Noriko Gotoh. Addiction to the NF-κB–triggered IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A27.
The 4Ps of Breast Cancer Chemoprevention: Putting Proven Principles into Practice
Authors: Jordan V. Craig 
Published: March 2017

Abstract
The pioneering Royal Marsden Tamoxifen Prevention Trial recruited 2,471 eligible high-risk women to be randomized to either placebo or tamoxifen (20 mg daily) for 8 years. Breast cancer incidence was evaluated at a median of 18.4 years from the start of the study. There was a 32% reduction in estrogen/progesterone receptor (ER/PR)–positive breast cancers after tamoxifen treatment finished. Translational research, to study “the good, the bad, and the ugly of tamoxifen” in the 1980s, subsequently ensured women's safety from possible increases in osteoperosis, coronary heart disease, and endometrial cancer. Other tamoxifen chemoprevention trials followed. The result of laboratory research was the unanticipated discovery of raloxifene to prevent osteoporosis and breast cancer at the same time. A new group of medicines, now known as selective ER modulators, was established. Indeed, the ability to prevent or delay multiple diseases with a single cheap medicine has the potential to alleviate pressure on health care systems that are overwhelmed. It is a priority to educate physicians appropriately to apply recommended proven medicines as preventives. Cancer Prev Res; 10(4); 219–22. ©2017 AACR.
See related article by Detre, et al., Cancer Prev Res 2017;10(3):171–6.