bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-09-17: Prognostic significance of progesterone receptor in hormonal receptor-positive breast cancer: Association with endocrine resistance
Authors: Bae SY , Lee SK , Lee JH , Lee H , Kim M , Kim J , Kil WH , Lee JE , Nam SJ 
Published: August 2014

Abstract
Background: Endocrine therapy has dramatic improvements of prognosis in patients with hormonal receptor positive breast cancer. However, long-term follow up shows that endocrine resistance is still major clinical concern. Although the value of estrogen receptor (ER) level can predict response to endocrine treatment in hormonal receptor positive breast cancers, few markers are available that can predict response to endocrine treatment. We attempted to identify molecular markers, especially progesterone receptor (PR), associated with endocrine failure in breast cancer.
Methods: We reviewed the medical records of 2513 breast cancer patients who underwent breast surgery and endocrine therapy at Samsung Medical Center between March 2007 and July 2011. Patients were compared according to ER and PR expression and to assess the clinical and biological features of ER+positive/PR-negative breast cancers to understand how PR might be a useful marker of these activities. ER and PR expression accessed using Allred score, the ‘positive” was defined that total score is larger than 2.
Results PR negative tumors were found more frequently in postmenopausal women (post- 11.2% vs. pre- 2.5%, P &lt; 0.001) and PR negative tumors were significantly associated with higher grade, higher level of Ki 67 and more expression of EGFR and CK5/6. In Kaplan-Meier analysis and multivariate analysis, PR negativity was significantly poorer prognostic factor of DFS (HR 3.1, 95% CI 1.2-8.2, P = 0.021) and OS (HR 89.8, 95% CI 3.4-2352.3, P = 0.007). Stratified by the menopausal status, there was not shown significant difference of survival between the PR+ and PR- tumor in postmenopausal women (DFS, HR 2.1, 95% CI 0.4-10.8, P = 0.381; OS, HR 10.6, 95% CI 0.6-171.4, P = 0.096). However, PR negative tumors showed an association with poor outcome in premenopausal women (DFS, HR 7.2, 95% CI 2.5-20.6, P &lt;0.001; OS, HR 24.6, 95% CI 2.2-275.6, P = 0.009).
Conclusion: In HR positive breast cancers, PR negative tumors were found more frequently in elderly, postmenopausal women. However, PR negative tumors are shown more aggressive and poorer survival than PR positive tumors despite of endocrine therapy, especially in premenopausal women.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-17.
Abstract P5-09-20: Development of a novel selective estrogen receptor down-regulator which shows efficacy in pre-clinical models of endocrine resistance
Authors: Weir H , Nardone A , Lawson M , Rowlinson R , Hulse M , Powell S , Callis R , Walker G , Curwen J , Wilson Z , Bradbury R , Rabow Al , de Savi C , Pazolli E , Reavey N , D'Cruz C , Schiff R 
Published: August 2014

Abstract
With over 70% of breast cancers expressing the estrogen receptor alpha (ERa), treatment with either anti-hormonal therapies that directly block ER function (e.g.Tamoxifen) or therapies that block the production of estrogen itself (e.g. aromatase inhibitors) are key to management of the disease. Despite initial efficacy seen with endocrine therapies, development of either de novo or acquired resistance ultimately limits the use of these agents although the majority of tumours continue to depend on ERα for growth. The ability to down regulate ER is particularly important in the endocrine resistance setting where ER appears to be activated in a ligand independent fashion by other growth factor signaling pathways. Agents such as Fulvestrant have been shown to offer additional benefit in the advanced setting due to its unique mechanism of binding and degradation of the ER receptor by the ubiquitin-proteosome complex. Given its low level of bioavailability and metabolic profile, Fulvestrant has been formulated as an intramuscular injection with 2 × 250mg monthly doses currently being tested clinically. We have sought to identify a novel, non-steroidal ERα antagonist and down-regulator that can be administered orally and could yield improved bioavailability and clinical benefit through enhanced biomarker modulation. We have identified a novel compound that can induce ERα degradation in breast cancer cell lines at picomolar concentrations with a similar half-life to Fulvestrant and is clearly differentiated from Tamoxifen which appears to stabilise ER protein. Due to good oral pharmacokinetic properties of the compound we have seen significant tumour efficacy in both tamoxifen-sensitive and -resistant models of breast cancer in vivo. In an MCF-7 model we have shown &gt;90% reduction in PR levels in a pharmacodynamic study and complete tumour growth inhibition (TGI) at 5mg/kg dose. Fulvestrant in the same model setting was unable to achieve &gt;60% PR inhibition at dose levels 3.8 fold greater than those achieved clinically with 500mg. We have also seen tumour regressions in a pre-clinical long term estrogen deprived (LTED) model, which mimic the aromatase resistance setting, and efficacy correlates with a significant decrease in ERα levels (&gt;60%). This orally bioavailable compound is progressing towards clinical evaluation and shows promise as a new SERD agent for the treatment of ER+ breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-20.
Abstract P5-10-03: Estrogen, obesity and mammary morphology in a middle-aged rat model of menopause
Authors: Liang J , Davis JD , Garcia AN , Wolfe A , Gore AC , Yin W 
Published: August 2014

Abstract
The risk of occurrence of breast cancer changes at menopause in women. Various studies propose an association between mammographic density and adipose tissue distribution in premenopausal and post-menopausal women. There is a positive correlation between mammographic density and visceral adiposity in post-menopausal women, but an inverse correlation of the two in premenopausal women. Similar findings have also been discovered in rodent models. To model the premenopausal and post-menopausal status in women, this study used a middle-aged ovariectomized (OVX) Sprague Dawley rat model, given 17b-estradiol (E2) or vehicle (VEH) capsule, E2-deprived rats. Rats were OVX at 11 mo, and given E2 or VEH for 3 or 6 mo. A subset of rats were initially given E2 or VEH for 3 mo, then switched to the opposite treatment for another 3 mo, to evaluate the importance of E2 timing/duration. Mammary tumorigenesis was monitored through the treatment. Tumors were surgically removed upon detection. Rats were euthanized at 14 months old (3 mo of treatment) or 17 months old (6 mo of treatment). The 4th mammary gland was whole mounted for mammarographic density studies and comparisions. Serum estradiol, progesterone and prolactin concentrations were measured. Our results showed: 1) Body weight and visceral fat significantly decreased in E2 compared to VEH treated rats. 2) Following 3 or 6 mo E2 treatment, 3/54 and 5/72 rats, respectively, developed palpable mammary tumors. By contrast, 0/54 and 1/72 rats developed palpable tumors following 3 or 6 mo VEH treatment. In the group given 3 mo VEH then switched to E2 for 3 mo, 2/18 rats developed tumors. 1/18 rats developed tumors in the group given 3 mo of E2 then switched to VEH for 3 mo. 3) Mammary gland whole mounts showed increased mammographic density and decreased fat pad in E2 treated group. 4) Serum prolactin concentration significantly increased in E2 compared to VEH treated rats at euthanization. These results suggest timing and duration of hormone treatments have differing effects on mammary morphology and tumorigenesis.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-10-03.
Abstract P5-11-04: Post-translational modification of the cell-fate factor Dachshund determines p53 binding and signaling modules in breast cancer
Authors: Pestell RG , Chen K , Wu K , Gormley M , Ertel A , Zhang W , Zhou J , DiSante G , Li Z , Rui H , Quong AA , McMahon SB , Deng H , Lisanti MP , Wang C 
Published: August 2014

Abstract
Breast cancer is a leading form of cancer in the world. Initially cloned as a dominant inhibitor of the hyperactive EGFR, Ellipse, in Drosophila, the mammalian DACH1 regulates expression of target genes in part through interacting with DNA-binding transcription factors (c-Jun, Smads, Six, ERα), and in part through intrinsic DNA-sequence specific binding to Forkhead binding sites. The Drosophila dac gene is a key member of the retinal determination gene network (RDGN), which also includes eyes absent (eya), ey, twin of eyeless (toy), teashirt (tsh) and sin oculis (so), that specifies eye tissue identity.
Several lines of evidence suggest DACH1 may function as a tumor suppressor. Clinical studies have demonstrated a correlation between poor prognosis and reduced expression of the cell-fate determination factor DACH1 in breast cancer, and loss of DACH1 expression has been observed in prostate and endometrial cancer. DACH1 inhibits breast cancer tumor metastasis and reduces breast cancer stem cell expansion via Sox2/Nanog. Although these studies suggest DACH1 may function as a tumor suppressor, the molecular mechanisms remain poorly defined. Herein, endogenous DACH1 co-localized with p53 in a nuclear, extranucleolar compartment and bound to p53 in human breast cancer cell lines, p53 and DACH1 bound common genes in ChIP-Seq. Full inhibition of breast cancer contact-independent growth by DACH1 required p53. The p53 breast cancer mutants R248Q and R273H, evaded DACH1 binding. DACH1 phosphorylation at serine residue (S439) inhibited p53 binding and phosphorylation at p53 amino-terminal sites (S15, S20) enhanced DACH1 binding. DACH1 binding to p53 was inhibited by NAD-dependent deacetylation via DACH1 K628. DACH1 repressed p21CIP1 and induced RAD51, an association found in basal breast cancer. DACH1 inhibits breast cancer cellular growth in an NAD and p53 dependent manner through direct protein-protein association.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-11-04.
Abstract P5-11-09: Crk II adaptor proteins as positive regulators of HER3 signaling in breast cancer
Authors: Dhupkar P , Zhao H , Mukherjee S , Mujoo K , Zhang N , An Z 
Published: August 2014

Abstract
HER3 (ErbB3), which is a member of the human epidermal growth factor receptor (EGFR) family has emerged as a key oncogene in cancer progression. HER3 overexpression has been observed in lung, prostate, melanomas and colon cancers and is associated with poor patient prognosis. HER3 has been known to play a role in resistance mechanisms towards EGFR tyrosine kinase inhibitors like Gefitinib and anti-HER2 antibodies like Trastuzumab in lung and breast cancers respectively. Upon ligand (neuregulin) binding, HER3 heterodimerizes with its partner receptors, inducing phosphorylation of its tyrosine residues in the c-terminal tail, which mediate HER3-dependent signaling. By binding to the HER3 c-terminal tail, Src homology 2 domain (SH2) or phosphotyrosine-binding (PTB) proteins may regulate the neuregulin-induced signaling. Here, we used a SH2 profiling approach to discover novel SH2 adaptor proteins interacting with HER3 and found that the SH2 adaptor protein Crk II (C10 regulator of kinase II) interacts strongly with phosphotyrosines in CHO cells overexpressing HER3 with or without neuregulin stimulation. Crk II and HER3 are critical in proliferation, migration and invasion of breast cancer cells. In this study, we investigate the protein-protein interaction of Crk II and HER3 in breast cancer. Our preliminary protein-protein interaction data confirmed that Crk II interacts with HER3 in MCF-7, MDA-MB-453 and MDA-MB-468 breast cancer cells. We hypothesize that Crk II affects HER3-induced signaling, thus affecting growth and migration in breast cancer cells.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-11-09.
Abstract P5-13-03: Factors associated with prophylactic mastectomy among BRCA-positive patients with no personal history of breast cancer
Authors: Elsayegh N , Gutierrez-Barrera A , Baum G , Muse K , Jackson M , Woodson A , Jessica P , Kuerer H , Litton J , Arun B 
Published: August 2014

Abstract
Background: The rate of prophylactic mastectomy (PM) has recently increased1. A deleterious mutation in the BRCA1 or BRCA 2 genes is among the major reasons why patients pursue PM 2, 3. Women with BRCA1 or BRCA2 gene mutations have up to an 87% risk to develop an invasive breast cancer (BC), and up to 45% risk for ovarian cancer (OC)2, 3. Most studies evaluating predictors of PM in BRCA mutation carriers are performed among women with breast cancer; however, accurate predictors for PM among unaffected BRCA mutation carriers are less defined. In a single institution study we aimed to evaluate predictors of PM among BRCA carriers with no personal history of breast cancer.
Method: One hundred seventy seven women with no personal history of BC, who tested positive for a BRCA1 or BRCA 2 germline mutation, were included in the study. Patients’ characteristics were obtained from a prospectively maintained research database under an IRB approved protocol at UT MD Anderson Cancer Center. Univariate analyses using chi-square and logistic regression analysis were used to determine predictive factors associated with PM. The patient characteristics examined included age, martial and educational status, bilateral salphingo-oophorectomy (BSO), family history of 1st and 2nd degree relatives with breast (BC) and ovarian cancer (OC), race, and BRCA genetic test result.
Results: Out of the 177 BRCA1 and BRCA 2 positive patients, 51 (29%) elected for PM. The average age for the cohort was 44 years (range 23-91). The majority were Caucasian (81%), and married (72%) with a college degree (64%). One hundred sixty-four (92%) patients had 1st and 2nd degree relatives with BC, 93 (53%) had 1st and 2nd degree relatives with OC, and 85 (48%) had undergone BSO. A logistic regression model was run to identify factors associated with undergoing PM, including family history of OC, family history of BC, BSO and age. Patients with a family history of OC were 2.5 times more likely than those without to have had a PM (p = 0.0125), and patients who had a BSO were 0.137 times less likely to have had a PM (p &lt;.0001). Only 12 patients did not have a family history of BC and none of those patients had a PM, so an Odds Ratio could not be calculated. However, it was determined through the Fisher's exact test that patients with a family history of BC were more likely to undergo a PM (p = 0.0198).
Conclusion: The rate of PM in our cohort was slightly lower than expected. Factors associated with PM included a family history of BC and OC. Interestingly, having had a BSO was associated with lower likelihood of undergoing PM (menopausal status will be further evaluated); possibly due to the knowledge that BSO reduces breast cancer risk.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-03.
Abstract P5-13-06: Seasonal variation in onset of inflammatory breast cancer: Evidence of an infectious trigger
Authors: Hashmi S , Liu Y , Bethony J , Cristofanilli M , Levine PH 
Published: August 2014

Abstract
Introduction:
Inflammatory breast cancer (IBC) is a rare but extraordinarily aggressive disease with a number of studies indicating that environmental factors play the most important role. We have identified four reported clusters of IBC and our investigations thus far suggest that local toxic or infectious agents could be involved in the pathogenesis of the disease. IBC, like Burkitt's lymphoma (BL) has been reported to cluster and both have been implicated with infectious agents. Since BL has been reported to have a seasonal variation attributed to acute malaria symptoms as the precipitating agent, we decided to investigate the seasonality of IBC in two populations.
Methods:
For our analysis we used the datasets of two IBC referral groups. The first group consisted of a series of 163 consecutive cases of patients seen at Fox Chase Cancer Center (FCCC) almost all being from the Northeast U.S. (NE) and Canada. At the time of initial visit a detailed series of questions was specifically directed at identifying the accurate time of the first onset of symptoms/signs including skin rash, swelling, pain, nipple retraction and palpable mass. The second was the IBC registry (IBCR), established at the George Washington University with the purpose of collecting standardized clinical and epidemiologic data (including a detailed interview) and biospecimens from patients with IBC in the U.S and Canada. Complete data on patients in both groups were evaluated, including diagnostic workup, pathologic findings and treatment.
Results:
Of the 163 FCCC patients, 156 had the month of onset of symptoms clearly delineated. Of the 161 patients in the IBCR, 153 had month of symptomatic onset defined. In the combined groups, 181 NE patients were compared with 63 from the South. A seasonal pattern was noted in the NE patients, a bimodal pattern showing most patients with onset in March and July-Sept. No seasonal pattern was noted in patients from the South.
Conclusion:
The reports of IBC clusters are consistent with an acute triggering factor, possibly an infection. The seasonality we observed in NE patients but not in southern patients is consistent with this hypothesis. We are currently continuing to investigate clusters of IBC and are testing for specific candidate infectious agents as well as candidate environmental toxic agents to further understand possible triggers for this disease.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-06.
Abstract P5-13-07: Genetic polymorphism of estrogen metabolizing enzyme CYP17A1 rs743572 impacts on serum testosterone level in Japanese premenopausal women
Authors: Yoshimoto N , Nishiyama T , Yamashita H , Takahashi S , Shiraki N , Sugiura H , Endo Y , Iwasa M , Asano T , Hato Y , Fujii Y , Toyama T 
Published: August 2014

Abstract
The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades. We recently demonstrated that this marked increase is mostly due to an increase in the estrogen receptor (ER)-positive subtype, and we created risk prediction models for ER-positive breast cancer in both pre- and post- menopausal women using genetic factors (single nucleotide polymorphism (SNP)), environmental risk factors, serum hormones and growth factors by logistic regression analysis. Serum level of testosterone, which is the precursor of estradiol in estradiol synthesis, was found to be a risk predictor in both pre- and post- menopausal women. On the other hand, it has been reported that some SNPs, including those of estrogen-related genes such as ESR1 and CYP17A1, are correlated with breast cancer risk by genome-wide association studies. To acquire some insights into this mechanism, we analyzed genetic factors (14 SNPs), serum hormones and growth factors (estradiol, testosterone, prolactin, insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3)) in 913 women with breast cancer and 278 disease-free controls for correlation between them.
Serum testosterone and prolactin levels were significantly higher in ER-positive breast cancer patients than in disease-free controls in both pre- (p&lt;0.0001, p&lt;0.0001) and post- (p&lt;0.0001, p = 0.007) menopausal women, and serum estradiol level was significantly higher in ER-positive breast cancer patients than in disease-free controls only in premenopausal women (p = 0.0005). There were significant differences in serum hormone levels among the women with each SNP genotype (homozygotes of major allele, heterozygotes and homozygotes of minor allele), including testosterone among rs743572 genotype (p = 0.014), estradiol among rs827421 genotype (p = 0.016), IGF-1 among rs6905370 genotype (p = 0.032), and prolactin among rs1042522 genotype (p = 0.035) in premenopausal women, as well as estradiol among rs3803662 genotype (p = 0.027) and IGFBP3 among rs6905370 genotype (p = 0.036) in postmenopausal women. In particular, serum testosterone level was significantly different among the rs743572, which is one of the enzymes that convert testosterone to estradiol, of genotypes (AA: 0.308 +/- 0.180 ng/ml, AG: 0.319 +/- 0.193 ng/ml and GG: 0.380 +/- 0.187 ng/ml, p = 0.014). On the other hand, the rs743572 heterozygotes of CYP17A1 have been reported to have increased breast cancer risk than homozygotes of both the major allele and minor allele in premenopausal women. Further studies are required to clarify this mechanism.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-07.
Abstract P5-13-10: Quality of care for premenopausal patients with early-onset breast cancer in Germany
Authors: Fischer D , Hedderich M , Heinrich A , Wedel B , Banz-Jansen C , Rody A , Waldmann A 
Published: August 2014

Abstract
Background and objective: The objective of the study is to evaluate how young breast cancer patients between 2002 and 2011 are treated adjuvantly and whether treatment adheres to the guidelines. The distinction between this cohort and a normally distributed cohort was verified.
Materials and methods: The study evaluates the data from a total of 2500 patients who were treated adjuvantly in the period from 2002 until 2011 and participated in a resident mother-child program. Until now, the data of 1053 patients have been analyzed. In cohort I (date of diagnose: 2002 - 2006) 535 women were analyzed, in cohort II (date of diagnose: 2010-2011) 518. The data includes TNM-stage, the biology of tumor, therapies and their guideline-adherence. In addition the amount of participation in studies was evaluated. All data were compared to an age-heterogeneous cohort from the state of Schleswig-Holstein and the DMP- report of the state of North Rhine-Westphalia (“older group”).
Results: The median age of the cohort I and II was 39 years. The median age of the age-heterogeneous groups was 59 years. 53% were diagnosed with stage pT1, 37% pT2, 7% pT3 or pT4. 49% of the patients in cohort I were pN0 (cohort II 58%), 31% pN1 (cohort II: 28%) and 20% (cohort II: 14%) had a more intense infestation of lymph nodes. The size of the tumors and the involvement of the lymph nodes were significant higher in the younger patients as in the older patients.
44% of the tumors showed G3, 34% were ER negative, 36% PR negative and 76% Her2 negative. 23% of the patients showed a triple negative carcinoma. The tumor biology was also worse in the younger patients than in the age-heterogeneous group.
All in all in cohort I 47% of the patients underwent mastectomie (cohort II:37%, older patients: 29%). 59% of the patients in cohort I with stage pT1 underwent breast-conserving surgery (cohort II: 69%, older group: 82%). Overall 15% of the women in cohort I received mastectomy with subsequent reconstruction (cohort II: 17%, older patients: 7%). 25% of the patients in cohort I received sentinel node biopsy only (cohort II 48%), 90% of the young patients received chemotherapy (older patients 59%), overall 21% of them were treated within studies. 51% of the young patients with antiendocrine therapy received GnRH-analoga, in the age of 40 years or younger 41%. The examination with regard to the conformity with guidelines showed a high guideline adherence in the younger group.
Conclusion: Young breast cancer patients provide a special challenge for the therapists because their prognosis is often worse because of a larger tumor and more metastatic lymph nodes as well as the worse tumor biology. They get a more aggressive therapy analogue to their worse situation. The therapies have a high guidelines adherence.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-10.