bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-05-09: Exploring bazedoxifene and palbociclib as potential therapeutic strategies for overcoming ESR1-mediated endocrine resistance
Authors: Nguyen M , Buchwalter G , Luo F , Garraway L , Brown M , Jeselsohn R 
Published: May 2016

Abstract
INTRODUCTION
Despite effective endocrine treatments, endocrine resistance remains a major clinical challenge. We and other groups have recently detected ligand-binding domain ESR1 mutations in metastatic estrogen receptor positive ( ER+) breast cancers. Our preclinical studies showed that these mutations confer constitutive activity and relative resistance to tamoxifen and fulvestrant. In this study we sought to investigate therapeutic strategies to overcome resistance rendered by the ESR1 mutations. Since our previous studies showed relative resistance to tamoxifen or fulvestrant, we hypothesized that bazedoxifene, a high affinity third generation SERM/SERD could overcome resistance driven by the ER mutant resistance. Additionally, we hypothesized that inhibiting cyclin D1, a key ER transcriptional target gene and cell cycle regulator, is a second potential therapeutic strategy to circumvent resistance rendered by mutant ER. Therefore in this study we tested the effects of bazedoxifene, palbciclib and their combination on cell proliferation in the presence and absence of the ESR1 mutations.
METHODS
For this study we established doxycycline inducible MCF7 cell lines expressing the ER-LBD mutations (Y537S, Y537N and D538G) and WT-ER as control. Cell proliferation response to bazedoxifene, tamoxifen, fulvestrant, palbociclib and the bazedoxifene-palbociclib combination was evaluated.
RESULTS
Cells harboring mutant ER were relatively resistant to tamoxifen and fulvestrant, as expected, and remained sensitive to single agent bazedoxifene and palbociclib. The combination of bazedoxifene and palbociclib was found to be superior to the single agents and exhibits synergistic activity.
CONCLUSION
The combination of bazedoxifene and palbociclib inhibits mutant ER cell growth and other cell models of endocrine resistance and is a potential therapeutic combination.
Citation Format: Nguyen M, Buchwalter G, Luo F, Garraway L, Brown M, Jeselsohn R. Exploring bazedoxifene and palbociclib as potential therapeutic strategies for overcoming ESR1-mediated endocrine resistance. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-09.
Abstract P3-05-10: Non-coding RNAs derived from near the ESR1 gene acts as a transcriptional regulator during estrogen deprivation adaptation of ER positive breast cancer cells
Authors: Fujiwara S , Saitoh N , Tomita S , Abdalla MO , Iwase H , Nakao M 
Published: May 2016

Abstract
Endocrine therapies that blocks estrogen production are effective for estrogen receptor (ER)-positive breast cancer. However, endocrine therapy treated patients eventually experience relapse after a long period of estrogen deprivation. The mechanism underlying acquisition of estrogen independent growth by ER positive breast cancer cells remains unclear.
To understand such molecular mechanism, we used a cell model LTED (long term estrogen deprivation) which MCF7 cells were cultured under estrogen deprivation for 4-10 months. In LTED cells, we found that ER encoded gene ESR1 was up-regulated and ER overproduction was essential for estrogen-independent cell growth. We also revealed that RNA transcriptions of the ESR1 and several neighbor genes were co-induced from both coding and non-coding regions in LTED cells, using RNA-sequence. These highly transcribed regions were corresponded to active histone modifications and transcription factor bindings according to publically available genome-wide analyses data. Fluorescence in situ hybridization (FISH) analyses indicated that RNA from the chromatin domain region nearby ESR1 were co-localized and made foci in nucleus.
We found non-coding regions that are particularly highly transcribed. FISH analyses indicated that RNAs from these regions might interact with the parental ESR1 gene locus. Recent studies have shown that non-coding RNAs are involved in transcriptional regulation and chromatin regulation. To understand the role of the non-coding RNA, we have generated MCF7 cells lines that lack the non-coding site, using CRISPR/CAS9 system. We found that mRNA transcription of multiple genes including ESR1 were impaired by the deletion. These findings suggested that these non-coding RNAs may be involved in chromatin regulation of the chromatin domain nearby ESR1.
In this study, we found non-coding RNAs that control transcription of chromatin domain genes in ER positive breast cancer cells. Such non-coding RNA mediated transcriptional regulation might be critical for endocrine therapy resistance adaptation.
Citation Format: Fujiwara S, Saitoh N, Tomita S, Abdalla MO, Iwase H, Nakao M. Non-coding RNAs derived from near the ESR1 gene acts as a transcriptional regulator during estrogen deprivation adaptation of ER positive breast cancer cells. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-10.
Abstract P3-05-15: Spatial and temporal genomic heterogeneity of estrogen receptor and clinical impact in a patient with advanced breast cancer
Authors: Rizel S , Dvir A , Soussan-Gutman L 
Published: May 2016

Abstract
Endocrine therapy targeting Estrogen receptor alpha (ERα) is a key therapeutic strategy for hormone-driven breast cancer. Resistance to endocrine therapy may be intrinsic, arising from different clones or acquired by evolution influenced by selective pressure conditioned by therapy. Emerging evidence points to the role of acquired ERα mutations in driving resistance, when detected in the metastases but were absent from primary tumor.
Here we studied tumor genomic evolution in a patient who developed two distinct recurrent consequences. The first recurrence was located at the lung and developed 14 years from diagnosis. In the adjuvant setting, the patient was treated with chemotherapy and had no endocrine therapy incorporated. On initial recurrence, the patient was treated with aromatase-inhibitor which resulted in complete response and the site is free of tumor now for 5.7 years. However, 2 years into endocrine therapy with aromatase-inhibitor the patient developed a single hepatic metastasis and treatment was changed to fulvestrant for 8 months with slow ongoing progression. The patient had partial hepatectomy, cholecystectomy and metastatectomy 3 months after fulvestrant was stopped. Histology and immunohistochemical stains confirmed breast origin, ER +2, 100%, PR +3, 100%.
The endocrine therapy resistant hepatic lesion was sequenced by hybrid capture Next Generation Sequencing (NGS) and ERα (D538G) mutation was detected along with PIK3CA and GATA3 typical for hormone+ breast cancer. We have studied the primary tumor by same NGS method and detected only the PIK3CA and GATA3 mutations. In the lung lesions, responsive for endocrine therapy when sequenced by NGS the ERα (D538G) resistant mutation was absent.
Clinical data for treatment of ERα (D538G) mutation driving endocrine resistance is lacking. The patient could not tolerate tamoxifen and failed treatments with aromatase-inhibitor and chemotherapy, losing 14 kg in weight. Treatment with megestrol acetate 160 mg was initiated and patient achieved partial response confirmed by hepatic MRI and an improved performance status which is now ongoing for 8 months.
This case represents the first evidence of heterogeneous response to endocrine therapy explained by presence/absence of ERα (D538G) resistant mutation along with evidence for an active treatment in not an uncommon scenario.
Citation Format: Rizel S, Dvir A, Soussan-Gutman L. Spatial and temporal genomic heterogeneity of estrogen receptor and clinical impact in a patient with advanced breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-15.
Abstract P3-06-14: DSS1 depletion is a promising strategy increasing chemosensitivity possibly independent of BRCA2 expression
Authors: Gondo N , Rezano A , Kuzushima K , Iwata H , Kuwahara K 
Published: May 2016

Abstract
Background
DSS1 (deleted in split-hand/split-foot malformation 1) was originally identified as a BRCA2-associated protein, and its downregulation results in the degradation of BRCA2. Some reports demonstrated that BRCA2 overexpression was correlated with histopathological grade III in sporadic breast cancers, implicating the involvement of BRCA2 overexpression in the proliferation rate of breast cancer cells. Because DSS1 is a stabilizer of BRCA2, we investigated whether altered expression of DSS1 was associated with malignant advancement of sporadic breast cancers. By comparison of DSS1 mRNA level, we reported that the high DSS1 expression groups in breast cancer patients showed worse prognosis in relapse-free survival; however, DSS1 expression per se was not correlated with other clinical parameters including cellular proliferation or tumor grade. Therefore, we hypothesized that breast cancer cells highly expressing DSS1 might be resistant to anti-cancer drugs, and compared chemosensitivity in overexpression or underexpression of DSS1 in breast cancer cells.
Methods
We established MCF7 overexpressing DSS1 (MCF7/DSS1) by retroviral transfection. DSS1 or BRCA2 knockdown in MCF7 was performed using siRNA transfection. The susceptibility to the cytotoxic chemotherapy such as doxorubicin and paclitaxel in breast cancer cells was analyzed by flow cytometry to detect apoptosis.
Results
MCF7/DSS1 showed more resistant to cytotoxic drugs compared with GFP-control MCF7 transfectants (MCF7/GFP). The percentages of apoptotic cells in MCF7/DSS1 and MCF7/GFP treated by doxorubicin were 40.2% and 12.0%, respectively. Conversely, depletion of DSS1 in breast cancer cells resulted in enhanced chemosensitivity compared to control cells. Although DSS1 knockdown induced the downregulation of BRCA2, BRCA2 depletion itself did not show such enhancement of chemosensitivity.
Conclusion
Consistent with the cohort study of sporadic breast cancers, we demonstrated that high expression of DSS1 increased resistance of breast cancer cells to cytotoxic chemotherapy in vitro. Conversely, DSS1 knockdown increased the susceptibility to these drugs in spite that BRCA2 depletion did not affect chemosensitivity. These results indicate that DSS1 could be a molecular target to increase chemosensitivity, which is independent of BRCA2 expression.
Citation Format: Gondo N, Rezano A, Kuzushima K, Iwata H, Kuwahara K. DSS1 depletion is a promising strategy increasing chemosensitivity possibly independent of BRCA2 expression. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-06-14.
Abstract P3-07-19: Progesterone receptor positivity is an independent predictor of long-term benefit from adjuvant tamoxifen treatment of estrogen receptor positive breast cancer
Authors: Fohlin H , Nordenskjöld A , Fornander T , Löfdahl B , Skoog L , Stål O 
Published: May 2016

Abstract
Introduction:The expression of estrogen receptor (ER) and progesterone receptor (PgR) predicts the response to endocrine therapy of breast cancer. Nearly all PgR positive tumors are also ER positive. The independent predictive information of PgR has been questioned after an overview by the EBCTCG. However, the studies in the overview were performed before modern PgR immunohistochemistry (IHC) was developed.
Purpose: We aim to investigate the independent predictive value of PgR determined by IHC in ER positive tumors.
Materials and methods: Between 1976 and 1990 the Stockholm Breast Cancer Study Group conducted a randomized trial comparing adjuvant tamoxifen versus control. We evaluated 618 patients with ER-positive "low-risk" breast cancer ( tumor size≤ 30 mm and lymph node-negative) for whom PgR was determined by immunohistochemistry. The median follow-up was 17 years. Hazard ratios (HRs) and 95 % confidence intervals (CIs) were estimated using the Cox's proportional hazards model.
Results: Patients with ER+/PgR+ tumors receiving tamoxifen had a reduced recurrence risk compared with those who were not treated with tamoxifen (HR= 0.40, 95% CI 0.27 – 0.59, p&lt; 0.001). For patients with ER+/PgR- tumors the difference between tamoxifen vs. no tamoxifen treatment was not statistically significant (HR= 0.88, 95% CI 0.51 – 1.52, p= 0.65). P for interaction between the groups was 0.02.
Tam vs. controlPgR (IHC)HR (95% CI)P valueP for interactionRecurrence-free survival≥ 10 %0.40 (0.27 - 0.59)&lt; 0.0010.02 &lt; 10 %0.88 (0.51 - 1.52)0.65 Distant recurrence-free survival≥ 10 %0.41 (0.25 - 0.65)&lt; 0.0010.08 &lt; 10 %0.80 (0.44 - 1.47)0.47 Breast-cancer specific survival≥ 10 %0.35 (0.21 - 0.60)&lt; 0.0010.11 &lt; 10 %0.70 (0.37 - 1.33)0.28
Conclusion: Our results indicate that the PgR expression adds predictive value to the ER expression regarding benefit from tamoxifen treatment.
Citation Format: Fohlin H, Nordenskjöld A, Fornander T, Löfdahl B, Skoog L, Stål O. Progesterone receptor positivity is an independent predictor of long-term benefit from adjuvant tamoxifen treatment of estrogen receptor positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-19.
Abstract P3-07-22: RS1008805 polymorphism in CYP19A1 gene is related to the efficacy of hormone therapy in early breast cancer
Authors: Wang X , Shao X , Zheng Y , Shi L , Huang Y 
Published: May 2016

Abstract
Purpose It has been suggested that genetic polymorphisms in CYP19A1 gene were related to aromatase activity as well as circulating steroid hormone levels in postmenopausal women. Therefore, it is biologically reasonable that CYP19A1 rs1008805 (A/G) polymorphism may be associated with clinical outcome for hormone therapy.
Methods Genotyping for CYP19A1 polymorphism rs1008805 was performed on 287 women with HR-positive early breast cancer. Associations were evaluated between CYP19A1 rs1008805 genotypes and disease-free survival (DFS).
Results Based on the analysis of the whole cohort, no significant differences were observed between rs1008805 genotypes and DFS, 5-year DFS rate. However, in postmenopausal women, rs1008805 genotypes were significantly associated with DFS and 5-years DFS rate (AA versus AG versus GG: 89.2 months versus 58.2 versus 32.7 months; 55.9% versus 47.8% versus 0%; P = 0.019). In addition, when the population was subgrouped into two cohorts, women carrying GG variant have a poorer DFS, 5-years DFS rate (GG versus AA or AG: 32.7 months versus 70.6 months; 0% versus 52.1%; HR, 3.613; 95% CI,1.380-9.457; P = 0.005). Furthermore, being adjusted by patients features in multivariate analyses, GG genotype remained an independent prognostic factor for DFS (HR, 3.439; 95% CI, 1.251-9.456; P = 0.017). However, there was no significant differences in DFS and 5-years DFS rate between women harbor the minor allele and those with the homozygous common allele (AG or GG versus AA: 52.4 months versus 89.2 months; 41.0% versus 52.9%; HR, 1.288; 95% CI, 0.705-2.353; P = 0.408). In addition, there were no differences between rs1008805 polymorphisms and DFS among premenopausal women.
Conclusions The homozygous minor allele (GG) of CYP19A1 rs1008805 is significantly associated with worse clinical outcome of hormone therapy in postmenopausal HR-positive early breast cancer patients. If confirmed, genotyping for CYP19A1 polymorphisms rs1008805 may provide predictive information for better selection of endocrine treatment.
Citation Format: Wang X, Shao X, Zheng Y, Shi L, Huang Y. RS1008805 polymorphism in CYP19A1 gene is related to the efficacy of hormone therapy in early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-22.
Abstract P3-07-31: Immune activation signatures identify a subset of ER+ breast cancers with increased pathologic complete response to neoadjuvant chemotherapy
Authors: Stover DG , Waks AG , Erica ML , Brugge JS , Winer EP , Selfors LM 
Published: May 2016

Abstract
Background: Proliferation is the strongest predictor of response to neoadjuvant chemotherapy in estrogen receptor-positive (ER+) breast cancer. Evidence of immune activation has also been associated with improved response to neoadjuvant chemotherapy in breast cancer. We hypothesized that immune signatures may be associated with response independent of proliferation in ER+ breast cancers.
Approach: We compiled microarray expression data from breast cancer biopsies obtained prior to neoadjuvant chemotherapy on 465 ER-positive/HER2-negative patients by reported pathologic receptor status. We evaluated the association of 118 published gene expression signatures with response to neoadjuvant chemotherapy, based on study-defined pathologic complete response (pCR) versus residual disease (RD).
Results: Overall, 42 of 118 signatures were significantly associated with response to neoadjuvant chemotherapy in ER+ breast cancer (FDR-corrected p&lt;0.05, simple logistic regression). Of those signatures that achieved significance, 52% (22/42) of signatures were proliferation-associated based on correlation to the 11-gene PAM50 proliferation index (Pearson's R2&gt;0.30, p&lt;1e-10). Among signatures that were NOT proliferation-associated, 50% (10/20) were immune-related. Using unsupervised hierarchical clustering of all 118 signatures, these ten immune signatures formed a distinct cluster. Of the 10 signatures, nine were designed to reflect "immune activation" and were highly correlated with each other in ER+ tumors (R2&gt;0.4, p&lt;0.001). The mean of each of these nine signatures was significantly higher in patients with pCR versus RD (FDR-corrected p&lt;0.05, t-test). Patients with higher "immune activation" signatures had increased likelihood of pCR within multiple subgroups of ER+ breast cancer, including luminal B and non-luminal PAM50 subgroups, as well as intermediate- and high-proliferation ER+ breast cancers. For luminal A or low-proliferation breast cancers, "immune activation" signatures were not significantly associated with response, though very few patients achieved pCR in these two subgroups.
Conclusions: Gene expression signatures associated with "immune activation" identify a subset of ER+ breast cancers with higher rates of pCR to neoadjuvant chemotherapy. These "immune activation" signatures appear to be proliferation-independent and may provide additional predictive information to existing gene expression-based approaches for ER+ breast cancer.
Citation Format: Stover DG, Waks AG, Erica ML, Brugge JS, Winer EP, Selfors LM. Immune activation signatures identify a subset of ER+ breast cancers with increased pathologic complete response to neoadjuvant chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-31.
Abstract P3-07-47: Comprehensive profiling of metaplastic breast carcinoma reveals frequent over-expression of PD-L1
Authors: Gatalica Z , Joneja U , Ghazalpour A , Swensen J , Feldman R , Cai F , Chen W , Xiao N , Reddy S , Palazzo J 
Published: May 2016

Abstract
Background: Metaplastic breast carcinoma (MBC) is a rare subtype of breast carcinoma less responsive to conventional chemotherapy relative to usual breast carcinomas (UBCs) such as ductal and lobular subtype. In molecular terms MBC usually clusters with triple negative breast cancer (TNBC), but MBCs portray a worse prognosis in comparison to TNBCs. Published studies investigating MBCs for specific biomarkers of therapy response are rare and limited by the methodological approaches.
Methods: This study included 132 patients with 38 histologically confirmed MBCs and 94 UBCs. Amongst the 94 UBCSs, 44 were estrogen receptor positive, 33 were triple negative and 17 were HER2 positive. Direct sequencing analysis was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tissue (FFPE) using the Illumina MiSeq Next Generation Sequencing platform (NGS). Immunohistochemistry for PD-L1 (SP142, Spring Bioscience), PD-1 (NAT105, Ventana) and EGFR (31G7, Life Technologies) was performed using automated procedures. Additionally, mutation analysis for EGFRvIII was performed on RNA extracted from FFPE tissue.
Results: At the genomic level, numerous cases of MBC had multiple genomic alterations with the most frequent genetic mutation in TP53 gene (14/24), similar to the TNBC controls (17/33). BRCA1 mutations were detected in 2/10 cases. Potentially actionable mutations were rare and included PIK3CA gene. Importantly, PD-L1 expression on cancer cells was detected in significantly higher proportion of MBCs (37%) than in the UBC cohort (6%) or TNBC control (14%) (p=3.7x10-5 and p=0.03, respectively). PD-1 positive tumors infiltrating lymphocytes (TILS) varied greatly in MBC (0 to &gt;50/mm2). Over-expression of EGFR was frequent in MBCs (62%); however no mutations in the gene including EGFRvIII were detected.
Conclusion: Comprehensive profiling of a large cohort of this rare carcinoma highlighted predominance of TP53 mutations, wild type EGFR gene expression, a distinct increase in proportion of PD-L1 expression in carcinoma cells, and PD-1 expression in TILS. The latter properties can be exploited in clinical trials utilizing immune check point inhibitors.
Citation Format: Gatalica Z, Joneja U, Ghazalpour A, Swensen J, Feldman R, Cai F, Chen W, Xiao N, Reddy S, Palazzo J. Comprehensive profiling of metaplastic breast carcinoma reveals frequent over-expression of PD-L1. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-47.