bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P1-02-09: Targeting breast cancer stem cell state equilibrium through modulation of redox signaling
Authors: Luo M , Shang L , Brooks M , Jiagge E , Zhu Y , Conley S , Fath MA , Harouaka R , Merajver SD , Spitz DR , Wicha MS 
Published: February 2018

Abstract
Breast cancer stem cells (BCSCs) maintain the plasticity to transition between quiescent mesenchymal- (M) and proliferative epithelial-like (E) states, but how this plasticity is regulated under metabolic/oxidative stress is poorly understood. Here, we show that M- and E-BCSCs exhibit markedly different sensitivities to the inhibitors of glycolysis and redox metabolism. Metabolic/Oxidative stress generated by 2DG/H2O2 or hypoxia promotes ROSlo M-BCSCs transition to their ROShi E-state. This transition is reversed by the antioxidant N-acetyl cysteine and facilitated by the activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust expression of NRF2/NFE2L2 and a wide variety of NRF2 downstream antioxidant responsive genes including the family of drug transporters and detoxification enzymes, NADPH production as well as the thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Suppression of NRF2 activity by a small-molecular inhibitor Trigonelline or shNRF2 mediated knockdown significantly decreased ALDH+ E- but not CD24-CD44+ M-BCSCs. This specific vulnerability of E-BCSCs to the inhibition of NRF2-mediated antioxidant defenses was also observed following inhibition of the downstream TXN and GSH antioxidant pathways, which promotes ROS-mediated differentiation and subsequent apoptosis of E-BCSCs. Co-inhibition of glycolysis and TXN/GSH pathways synergistically suppressed tumor growth and tumor initiating potential in two patient-derived xenograft models of triple negative breast cancer by eliminating both M- and E-BCSCs. Together, our studies reveal novel cellular and molecular mechanisms demonstrating how modulation of redox signaling regulates the equilibrium of two distinct BCSC states. These studies define the metabolic vulnerabilities of M- and E-BCSCs, and also provide a novel therapeutic approach to collectively target these distinct CSC states. As the CSC state equilibrium may be similarly regulated across a spectrum of tumors with diverse oncogenic drivers, this approach may have broad therapeutic applicability.
Citation Format: Luo M, Shang L, Brooks M, Jiagge E, Zhu Y, Conley S, Fath MA, Harouaka R, Merajver SD, Spitz DR, Wicha MS. Targeting breast cancer stem cell state equilibrium through modulation of redox signaling [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-02-09.
Abstract P1-06-03: Breast cancer-specific survival (BCSS) in SEER patients with 21-gene Recurrence Score® (RS) results &lt;11 classified as prognostic stage IA by new 8th edition AJCC staging manual
Authors: Baehner FL , Petkov VI , McCullough D , Shak S 
Published: February 2018

Abstract
Introduction: The 8th edition of the AJCC Staging Manual added molecular features for the first time and now includes ER, PR, HER2, and the 21-gene assay for prognostic staging. We obtained real-world evidence of BCSS by age, tumor size, and grade in a population-based SEER analysis of N0, HR+, HER2-negative breast cancer and RS &lt;11 (tumor size up to 5 cm) to obtain more detailed information on clinically “unfavorable” subgroups.
Methods: RS results were provided to SEER registries as mandated by their methods for linkage (Petkov npj Breast Cancer 2016). Patients (pts) with RS &lt;11 and size up to 5 cm were eligible if N0, HR+, HER2-negative, had no prior malignancy, and were diagnosed between Jan 2004 and Dec 2012 (SEER survival updated through 2013). 5-year BCSS was estimated using actuarial methods.
Results: 9,304 pts had RS &lt;11 (19% of those meeting all other eligibility), with median follow-up of 40 months. Median age was 59 y, with 22% &lt;50 y and 16% ≥70 y. Tumor size was &gt;2 cm in 21% of pts. Tumor grade was moderate in 54% and poor in 8% of pts. Overall, 5-year BCSS for pts with RS &lt;11 was 99.6% (95% CI 99.4%, 99.7%), with reported chemotherapy (CT) use in 3.3% of pts. In contrast, BCSS for pts with RS &gt;25 and RS ≥31 was 3.5% and 4.7%, respectively, with frequent CT use. 5-year BCSS for important clinicopathologic subgroups show high 5-year BCSS despite “unfavorable” age, tumor size, and grade (Table).
5-y BCSS for RS &lt;11, by Clinicopathologic FactorsRS &lt;11 and Age &lt;50 yRS &lt;11 and Tumor Size 2.1-5.0 cmRS &lt;11 and Poor Tumor GradeN (% of N with CT ‘Yes’)5-y BCSS (95% CI)N (% of N with CT ‘Yes’)5-y BCSS (95% CI)N (% of N with CT ‘Yes’)5-y BCSS (95% CI)2009 (6.2%)100% (100%, 100%)1976 (5.5%)99.3% (98.5%, 99.7%)686 (5.8%)99.5% (97.9%, 99.9%)
Conclusions: In this SEER population-based study, pts with RS &lt;11 had a wide range of clinicopathologic features. 5-year BCSS was high (&gt;99%), regardless of age, tumor size, or grade. These results support the new AJCC staging criteria that classify N0, HR+, HER2-negative pts with RS &lt;11 and tumor size up to 5 cm as having Prognostic Stage IA disease.
Citation Format: Baehner FL, Petkov VI, McCullough D, Shak S. Breast cancer-specific survival (BCSS) in SEER patients with 21-gene Recurrence Score® (RS) results &lt;11 classified as prognostic stage IA by new 8th edition AJCC staging manual [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-06-03.
Abstract P1-07-10: Molecular subtypes of triple negative breast cancer have different sensitivity signature to established chemotherapy agents
Authors: Győrffy B , Nagy Á , Santarpia L , Hatzis C 
Published: February 2018

Abstract
Background: Triple negative breast cancer (TNBC, ER/PR/HER2 negative) patients have the worst prognosis among all breast cancer patients. Recently, six molecular subtypes have been proposed to sub-divide TNBC into clinically relevant sub-cohorts. It is unknown whether these molecular subtypes have different sensitivity against known chemotherapy agents. Here, we identified the cross-section of predictive and prognostic genes in a large TNBC dataset.
Methods: An integrated database comprising 2,071 TNBC patients with transcriptome-level gene expression data and clinical follow-up was set up from 52 different GEO and EGA datasets. The database included n=418 basal-like 1, n=170 basal-like 2, n=465 immunomodulatory, n=384 mesenchymal, n=207 mesenchymal stem-like, and n=427 luminal androgen receptor samples. The prognosis was computed for all genes (n=54,675) in each of the six subtypes separately using Cox proportional hazards regression. Another database (n=1,641) was set up for tumors with known therapy response as defined by pathological complete response (PCR) – in this, the correlation to response against a taxanes/anthracycline chemotherapy was computed using Mann-Whitney analysis. The overlap between the two datasets was determined at p&lt;0.0001.
Results: The proportion of responder patients was lowest in basal like 2 subtype. There were more genes significant for response to anthracyclines (n=6,118) than to taxanes (n=3,927). When comparing each subtype separately, most genes were prognostic in basal-like 1 and luminal androgen receptor subtypes (n=73/110 and n=73/111 respectively for taxane/anthracycline response genes). Almost no genes were overlapping to the immunmodulatory and mesenchymal stem-like subtypes (n=8/14 and n=3/7, respectively). When comparing anthracycline and taxane treatment across all six subtypes, there was no significant difference. We have to note that the different sample sizes in the different TNBC cohorts provide different power to detect an association.
Discussion: Based on our results, TNBC tumors in the basal-like 1 and luminal androgen receptors are most likely to benefit from chemotherapy while there is no difference for the selection between the two most common agents.
Citation Format: Győrffy B, Nagy Á, Santarpia L, Hatzis C. Molecular subtypes of triple negative breast cancer have different sensitivity signature to established chemotherapy agents [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-10.
Abstract P1-07-27: Prognostic value of programmed death 1/Programmed death ligand 1/ mammalian target of rapamycin/Rictor/Tuberin in human breast cancer
Authors: Uhercik M , Sanders AJ , Owen S , Davies EL , Sharma AK , Jiang WG , Mokbel K 
Published: February 2018

Abstract
Background:The Mammalian Target of Rapamycin (mTOR) regulates a multitude of cellular processes including metabolism, proliferation and growth. It is known to form two multi-protein complexes - complex 1 (mTORC1) and complex 2 (mTORC2) with Raptor and Rictor being their core proteins vital for their integrity.
Tuberin, the product of the Tuberous Sclerosis Complex gene 2, TSC2, has been characterized as a tumour suppressor and negatively regulates the mTOR pathway.
Programmed Death 1 (PD-1), a transmembrane protein particularly expressed on the surface of tumour cells, acts as an immune checkpoint receptor. Together with its ligand Programmed Death Ligand 1 (PDL-1) they form a pathway which when activated influences anti-tumour immunity and supresses anti-tumour adaptive responses. The expression of PD1/PDL-1 is lightly regulated by the mTOR pathway.
We investigated the value of expression patterns of all these molecules in breast cancer as potential prognostic factors.
Materials and Methods: Quantitative PCR (qPCR) analysis was used to determine the transcript expression profile of the five genes of interest (PD-1, PDL-1, mTOR, Rictor and Tuberin) in 128 breast cancer specimens.The correlation between PD-1 or PDL-1 with mTOR, Rictor and Tuberin was assessed using the Spearman Rank Order Correlation. Subsequently, a combined analysis was performed, where the influence of favourable expression in relation to patient overall (OS) and disease free survival (DFS) using the Kaplan Meier survival curves and multivariate analysis.
Results: The mRNA expression of the molecules showed a varying degree of association with the clinicopathological parameters. PD-1 transcript expression showed a significant correlation with mTOR expression (p &lt; 0.001). PDL-1 transcript expression was seen to correlate with mTOR (p &lt; 0.001), Rictor (p &lt; 0.001) and Tuberin (p &lt; 0.01) transcript expression. However, when the expression profile was analysed using an integrated expression score, the combined predictive value for the clinical outcome of the five genes was highly significant in terms of OS (p &lt; 0.001) and DFS (p = 0.001), and was found to be an independent prognostic factor (p&lt;0.001) for breast cancer related death using a multivariate analysis.
Conclusions: Our study identifies a molecular signature of 5 genes as a powerful prognostic predictor of OS and DFS in patients with breast cancer.
Citation Format: Uhercik M, Sanders AJ, Owen S, Davies EL, Sharma AK, Jiang WG, Mokbel K. Prognostic value of programmed death 1/Programmed death ligand 1/ mammalian target of rapamycin/Rictor/Tuberin in human breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-27.
Abstract P1-07-29: Clinicopathologic characteristics and prognostic factors of pure mucinous breast cancer
Authors: Gwark SC , Lee JW , Lee SB , Sohn G , Kim J , Chung IY , Kim HJ , Ko BS , Son BH , Ahn SH 
Published: February 2018

Abstract
Background: Mucinous carcinoma of the breast is a uncommon particular type of breast cancer and comprises approximately 4% of all invasive breast cancers. It is charactarized by abundant extracellular mucin production and present a more favorable prognosis than IDC-NOS. Pathologically, mucinous carcinoma is divided into two subtypes : pure and mixed. In this study, we reviewed the clinicopathologic characteristics and prognostic factors of pure mucinous carcinoma.
Methods: We reviewed the 23 years cumulative data of pure mucinous breast cancer patients from database of the Breast Cancer Center at ASAN medical center, Korea, between 1989-2011, retrospectively. Total 386 pure mucinous carcinoma cases were reviewed to analyze clinicopathologic characteristics and prognosis.
Result: Total of 386 patients with pure mucinous breast cancer were identified. Mean age was 46.7. 149 patients underwent modified radical mastectomy and 236 underwent breast-conserving therapy. The T-stage was T1 in 187 patients, T2 in 178 patients, T3 in 17 patient and T4 in 4 patients. Node negative was 325 and node positive was 61. Estrogen receptor was positive in 342 and negative in 29. Progesterone receptor was positive in 276 and negative in 95. HER-2 was positive in 47 and negative in 273. 152 patients received adjuvant chemotherapy and 240 patients received adjuvant radiotherapy. 351 patients received hormone therapy and among these patients, 231 patients were treated with Tamoxifen alone, 81 were Tamoxifen with ovarian function suppression, 37 were AI only and one patient was ovarian function suppression only. The 5 year disease free survival rate was 93.3%, 5 year cancer specific survival rate was 98.2% and 5 year overall survival rate was 96.6%. Univariate analysis showed that ER status, nodal status and Her2 status were appear to be prognostic factor of Disease free survival rate. Using Cox regression, result of multivariate analysis revealed that only nodal status is the most significant prognostic factor for survival rate.
Conclusions: Pure mucinous carcinoma of the breast is a rare subtype with a favorable prognosis. Nodal status rather than ER status, Her2 status are considered to be the most significant prognostic factor of pure mucinos breast cancer.
Citation Format: Gwark SC, Lee JW, Lee SB, Sohn G, Kim J, Chung IY, Kim HJ, Ko BS, Son BH, Ahn SH. Clinicopathologic characteristics and prognostic factors of pure mucinous breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-29.
Abstract P1-07-33: Impact of family history of breast and/or ovarian cancer in triple negative breast cancer
Authors: Morante Z , De la Cruz-Ku G , Pinto J , Enriquez D , Lujan M , Luque R , Eyzaguirre E , Saavedra A , Fuentes H , Neciosup S , Gomez H 
Published: February 2018

Abstract
Background: A family history of breast and/or ovarian cancer (FHBOC) is a risk factor for breast cancer. The influence of FHBOC in the prognosis of triple-negative breast cancer (TNBC) is controversial. The aim of this study was to analyze the impact of FHBOC on the prognosis in TNBC patients.
Methods: We retrospectively reviewed a database of patients diagnosed of TNBC (period 2000-2014) and treated at “Instituto Nacional de Enfermedades Neoplasicas”. The patients were divided into two groups: with FHBOC and non-FHBOC. The clinical features and prognosis between groups were compared. Disease-free survival (DFS) and overall survival (OS) differences were calculated by the Kaplan-Meier Method and differences were evaluated by the Log- Rank test. Prognostic factors were identified by the Cox regression analysis.
Results: Overall, 266 out of 2007 TNBC patients, had +FHBOC (13.3%). The median age for the general population was 49 years. Compared with the non-FHBOC group (51.1%), the 43.8% +FHBOC were premenopausal. Prevalence of +FHBOC in a first-, second- and a third-degree relative was 26.8%, 28.5%, and 44.7%, respectively. Regarding histological subtype, invasive ductal carcinoma was the most prevalent (93.5%). Clinical stages (CS) II/III was more frequent in both groups (86.3 vs. 86.1). A total of 59% of FHBOC patients underwent surgery and 52% for non-FHBOC (p=0.029- Conservative 41.1 vs. 30.7 - Mastectomy 58.9 vs. 69.3). The median of follow-up was 9 years. DFS rate was higher in FHBOC patients (53.6% vs. 42.9%, p=0.001). OS was significantly better In the FHBOC group (Table 1). In the multivariate analysis, poor prognosis variables to DFS were an advanced age at diagnosis (≥50 years) (p=0.006) and higher clinical stage (CS I vs. CS III, p&lt;0.001) while chemotherapy (CT) and radiotherapy (RT) were associated with an improved DFS. In regard to the OS, FHBOC was associated with a better prognosis (HR:0.77, 95%CI:0.62- 0.95, p=0.016).
Conclusion: Our results showed a better prognosis in TNBC patients with family history of breast and/or ovarian cancer in terms of DFS and OS.
Table 1. +FHBOC group (DFS/OS rates) +FHBOCnon-FHBOCTotalPDFS (%) 5-years7162630.03210-years635052 OS (%) 5-years665455&lt;0.00110-years584750
Citation Format: Morante Z, De la Cruz-Ku G, Pinto J, Enriquez D, Lujan M, Luque R, Eyzaguirre E, Saavedra A, Fuentes H, Neciosup S, Gomez H. Impact of family history of breast and/or ovarian cancer in triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-33.
Abstract P1-07-34: Clinical outcomes of single versus double hormone receptor positive breast cancer patients treated with neoadjuvant chemotherapy
Authors: Raphael J , Nofech-Mozes S , Trudeau ME 
Published: February 2018

Abstract
Purpose
This study aimed to evaluate and compare tumor response rates and survival outcomes between single and double hormone receptor (HR) positive (+) [Estrogen Receptor (ER+)/Progesterone Receptor (PR) negative (-) or ER-/PR+ versus ER+/PR+] breast cancer (BC) patients with any HER2 status treated with neoadjuvant chemotherapy at a single institution
Methods
A retrospective review was conducted using the Sunnybrook “Biomatrix” database to identify eligible patients. A multivariable logistic regression analysis (MLR) was performed to assess the association between HR status (single or double HR+) and pathologic complete response (pCR) rates at surgery. A Kaplan-Meier method was used to estimate Disease Free Survival (DFS) and a log-rank test was used to compare DFS between 3 subgroups of patients: single or double HR+ and HR negative patients
Results
Three hundred and four BC patients were identified and included in the analysis with a median follow up of 43.3months (Q1-Q3: 28.7-61.1) and a mean age of 49.7 years (Standard deviation 10.9). Forty seven percent (47/101), 31% (11/36) and 14% (24/167) of patients with HR negative, single HR+ and double HR+ disease achieved a pCR respectively (X2 test &lt;0.0001). In a MLR analysis, HR status and HER2 status were associated with pCR rates. Compared to HR negative patients, patients with double HR+ disease were less likely to achieve pCR (Odd ratio (OR):0.14, 95%CI 0.06-0.31, p&lt;0.0001) while single HR+ patients did not differ (OR:0.51, 95%CI 0.19-1.4). The association between HR+ status (single versus double HR+) and pCR rates compared to HR negative patients remained the same in subgroup analyses of HER2+ and HER2 negative patients separately. No difference in survival (DFS) was seen between the 3 subgroups of patients: HR negative, single and double HR+ patients.
Conclusion
BC patients with single HR+ disease behave differently than double HR+ patients in terms of likelihood of achieving pCR after neoadjuvant chemotherapy and do not differ from HR negative patients. This difference does not translate into a difference in DFS. Prospective studies are needed to validate these findings before considering different treatment strategies for these 2 subgroups of HR+ BC patients.
Citation Format: Raphael J, Nofech-Mozes S, Trudeau ME. Clinical outcomes of single versus double hormone receptor positive breast cancer patients treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-34.
Abstract P1-09-09: Efficacy of estrogen receptor β agonists in the prevention of breast cancer progression to therapy resistance
Authors: Ramasamy K , Samayoa C , Krishnegowda NK , Vadlamudi RK , Tekmal RR 
Published: February 2018

Abstract
Estrogen plays an important role in the initiation and progression of breast cancer (BCa). Approximately, 70% of breast tumors are estrogen receptor (ER) positive at the time of presentation. Endocrine therapy using aromatase inhibitors (AI), or anti-estrogen (AE) molecules are widely used for treating ER+ve BCa. However, their efficacy is limited by intrinsic and acquired therapy resistance and most patients develop resistance to these drugs. The transcriptional effects of estrogen are mediated by two ERs (ERα and ERβ) and both are expressed in normal breast tissue. Unlike ERα, ERβ functions as tumor suppressor. However, role of ERβ specific agonists in the prevention of BCa progression remains elusive. In this study, we investigated the effectiveness of two ERβ agonists (S-Equol and LY500307) in the prevention of BCa progression using endocrine therapy sensitive (MCF7-aro) and letrozole resistant (MCF7-aro-LTLT) cells. Our results demonstrated that treatment with ERβ agonists inhibit short-and long-term growth of both endocrine therapy sensitive and resistant BCa cells. In addition, ERβ agonists treatment inhibited invasion and migration of both MCF7-aro and MCF7-aro-LTLT cells. Importantly, cell cycle analysis revealed that ERβ agonists induced cell cycle arrest. Our gene microarray analysis demonstrated that both ERβ agonists significantly modulated genes involved in the cell cycle progression, DNA replication and cell death pathways. Further, gene enrichment analysis of differentially expressed genes revealed that genes involved in the cell cycle checkpoints emerged as significant pathway modulated by ERβ agonists treatment in MCF7-aro cells. Interestingly, in letrozole-resistant MCF7-aro cells, DNA replication was significantly affected by ERβ agonists treatment. Pathway analysis also identified enrichment for chemokine signaling pathways. We confirmed pathway analysis by qRT-PCR and western blot analysis. Accordingly, treatment of in vivo syngeneic xenografts with ERβ agonists significantly inhibited BCa progression. Collectively, these results from this study suggest that ERβ agonists have potential to prevent the progression of BCa progression.
Citation Format: Ramasamy K, Samayoa C, Krishnegowda NK, Vadlamudi RK, Tekmal RR. Efficacy of estrogen receptor β agonists in the prevention of breast cancer progression to therapy resistance [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-09-09.