bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-06-05: Down-regulation of the circadian factor Period 2 by the oncogenic E3 ligase Mdm2: Relevance of circadian components for cell cycle progression
Authors: Liu J , Gotoh T , Vila-Caballer M , Santos CS , Yang J , Finkielstein CV 
Published: August 2014

Abstract
Circadian rhythms are mechanisms that measure time on a scale of about 24 h and that adjusts our body to external environmental signals. Core circadian clock genes are defined as genes whose protein products are necessary components for the generation and regulation of circadian rhythms. Circadian proteins also regulate genes involved in either cell division or death; and a perturbation of the balance among these processes leads to cancer development and progression.
A key aspect of cancer research is identifying new regulatory pathways involved in proliferation and differentiation of cell. Disruption of circadian rhythm has recently emerged as a new potential risk factor in the development of cancer, pointing to the core gene period 2 (per2) as a tumor suppressor. However, it remains unclear how the circadian network regulates tumor suppression, nor which, if any, of its components is either the ultimate effector that influences the fate of the cell.
Initial experiments were devoted to identifying new interacting partners for Per2 using a two-hybrid system. Interestingly, among the positive clones analyzed was the oncogenic protein Mdm2. This result was validated by immunoprecipitation of recombinant and endogenous Per2/Mdm2 complexes from unstressed cells. Pull-down assays using tagged-expressed proteins fragments and labeled proteins were later used to map the interacting regions between Per2 and Mdm2. Our results show Mdm2 binds to the central flexible region of Per2 known to interact with various protein partners. Thus, we hypothesized that binding of Mdm2 to Per2 might act by mediating its ubiquitination and therefore altering Per2 stability. We next examined the formation of the Mdm2/p53/Per2 complex by immunoprecipitation. Our data show anti-p53 antibody is able to co-immunoprecipitate Per2 and Mdm2. Moreover, in vitro and in vivo ubiquitination assays show that binding of Per2 to p53 prevented ubiquitination of p53 by Mdm2 without altering their binding. Immunofluorescence studies using H1299 cells (p53-) confirmed Per2 role in p53 stabilization and for localization. Overall our results suggest that Mdm2 modulates the stability of Per2 and p53 in unstressed cells, and might be responsible for the oscillatory levels of these proteins observed in a 24 h cycle.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-06-05.
Abstract P6-06-06: The therapeutic potential and hazard of exposure to Cerbera odollam leaf extracts
Authors: Chung F , Chan K , Lim YY , Li B 
Published: August 2014

Abstract
Background: Despite its significance in leading to the reduction of breast cancer mortality rates, therapeutic regiments for breast cancer still face two major problems: (1) the heterogeneity of the tumours and (2) the prevalence of drug resistance towards anti-estrogen therapy. The leaf extracts from Cerbera odollam were screened for active compounds with the potential to overcome these problems.
Methods: Hormone responsive (MCF7) and hormone-independent cell lines (MDA-MB-231) were treated with the fractionated methanolic extracts of C. odollam followed by analyses on cell cycle perturbations and gene expression changes resulting from the treatment. The stated analyses were performed by flow cytometry, semi-quantitative RT-PCR, western blotting and immunofluorescence. The active fraction was identified, upon which HPLC separation was performed to identify the putative active compound.
Results: Initial experiments revealed that a fractionated extract contains a potent cytostatic agent which is active towards hormone-responsive but not hormone-independent breast cell lines [the Estrogen Receptor-alpha (ERα) positive MCF7 cells remained static in growth for 10 days]. Comparison of the effects of the active and inactive fractions on MCF7 cells revealed key differences in cell growth and expression of ERα and its downstream regulated genes. The active compound was identified to be neriifolin (a cardiac glycoside) which also exhibited prolonged cytostatic effects (for 10 days upon treatment of 18.7 nM) similar to the active fraction. Gene expression analyses suggested that the ERα/Estrogen (E2) regulatory pathway and p53-dependent p21WAF1 transactivaton could be the cellular targets.
Conclusion: Although neriifolin could be a potential drug for breast cancer treatment, its severity in down regulation of the ERα/E2 regulatory pathway which is critical during female development indicates the potential health hazard from our exposure to C. odollam. We are now focusing on establishing assay to evaluate whether neriifolin could cause drug resistance (similar to tamoxifen) by silencing ERα expression through hypermethylation of the ERα promoter.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-06-06.
Abstract P6-07-01: Prognostic impact of the 21-gene Recurrence Score (RS) on loco-regional recurrence (LRR) of node-positive, ER-positive breast cancer patients (pts) treated with adjuvant chemotherapy: Results from NSABP B-28
Authors: Mamounas Eleftherios P , Tang Gong , Paik Soonmyung , Baehner Frederick L , Liu Qing , Jeong Jong-Hyeon , Kim Seong-Rim , Butler Steven M , Jamshidian Farid , Cherbavaz Diana B , Sing Amy P , Shak Steven , Julian Thomas B , Lembersky Barry C , Wickerham D Lawrence , Costantino Joseph P , Wolmark Norman 
Published: August 2014

Abstract
Withdrawn by Author
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-01.
Abstract P6-07-02: Prediction of oncotype DX® recurrence score using pathology generated equations
Authors: Bhargava R , Klein ME , Shuai Y , Brufsky AM , Puhalla SL , Jankowitz R , Dabbs DJ 
Published: August 2014

Abstract
BACKGROUND: Oncotype DX® is a quantitative reverse transcription polymerase chain reaction based assay that has been shown to have prognostic and predictive value in estrogen receptor (ER) positive breast cancers. The result is reported as a recurrence score (RS) ranging from 0–100, divided into low risk (&lt;18), intermediate risk (18–30), and high risk (≥31) categories. Prior studies have shown that RS is influenced by ER and progesterone receptor (PR) expression, HER2 status, proliferation index, and tumor grade. Our pilot study showed that RS can be predicted by an equation incorporating standard morpho-immunohistologic variables (referred to as Original Magee Equation; Mod Pathol. 2008;21:1255–1261).
METHODS: Using a dataset of 817 cases, we formulated three additional equations to predict the RS category for an independent set of 255 cases. Three models were built based on different hypotheses and data availability and are represented below.
New Magee Equation 1 (nME1): RS = 15.31385 + Nottingham score*1.4055+ ER H-score*(−0.01924) + PR H-score*(−0.02925) + (0 for HER2 negative, 0.77681 for equivocal, 11.58134 for HER2 positive) + Tumor size*0.78677 + KI67 index*0.13269.
New Magee Equation 2 (nME2): RS = 18.8042+ Nottingham score*2.34123 + ER H-score*(−0.03749) + PR H-score*(−0.03065) + (0 for HER2 negative, 1.82921 for equivocal, 11.51378 for HER2 positive) + Tumor size*0.04267.
New Magee Equation 3 (nME3): RS = 24.30812+ ER H-score*(−0.02177) + PR H-score*(−0.02884) + (0 for HER2 negative, 1.46495 for equivocal, 12.75525 for HER2 positive) + KI-67*0.18649.
RESULTS: The concordance between the risk category of oncotype DX® and our equations was 55.8%, 59.4%, and 54.4% for nME1, nME2, and nME3 respectively. With exclusion of the intermediate risk categories for both the actual RS and estimated RS, the concordance for each equation increased to more than 95%, reflecting the very low two step discordance (100% {76/76}, 98.6% {75/76}, and 98.7% {79/80} for nME1, nME2, and nME3 respectively). Even when the estimated RS fell in the intermediate category with any of the equations, the actual RS was either intermediate or low in more than 85% of the cases. The Pearson correlation coefficient between estimated and actual RS was similar for each of the equations (0.61661, 0.60386 and 0.59407 for nME1, nME2 and nME3, respectively).
CONCLUSIONS: Any of the 3 equations can be used to estimate the RS depending on available data. If the estimated RS is clearly high or low, the oncologists should not expect a dramatically different result from oncotype DX®, and the oncotype DX® test may not be needed. Conversely, an oncotype DX® result that is dramatically different from what is expected based on standard morpho-immunohistologic variables should be thoroughly investigated.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-02.
Abstract P6-07-03: Risk classification of Early Stage Breast Cancer as Assessed by MammaPrint and Oncotype DX Genomic Assays
Authors: Clough KB , Poulet B , Jamshidian F , Butler S , Svedman C , Levy E 
Published: August 2014

Abstract
Background: The 21-gene Oncotype DX® Recurrence Score® assay has been validated for prediction of 10-year risk of distant recurrence and likelihood of benefit from chemotherapy (CT) in patients (Pts) with estrogen receptor-positive (ER+) early stage breast cancer (ESBC). MammaPrint® is a multi-gene assay that has been validated as a prognosticator in a heterogenous Pt population that includes ER+, ER−, triple negative and HER2+ Pts. While the development and validation cohorts for these genomic assays are significantly different, the tests are frequently believed to provide equivalent information. The aim of the present study was to assess how these tests classify patients when compared side by side in the same Pt specimen.
Materials and methods: Pts with ER+, HER2−, ESBC in which the MammaPrint assay had been sent were identified at the Institut du Sein, Paris, France. Clinical and pathological characteristics and the MammaPrint results (failure, low or high risk) were collected. Oncotype DX quantitative RT-PCR analysis was performed at Genomic Health and was blinded to the clinical and MammaPrint data. Descriptive statistics were calculated for failure rates, cross classification, and tumor characteristics.
Results: Informed consent and sufficient tumor material for analysis was available from 67 Pts who were predominantly low and intermediate risk by clinicopathologic features: Tumor grade- 24 low, 36 intermediate and 7 high; Histology- 49 ductal, 14 lobular and 4 other. MammaPrint analysis had failed to deliver result for 10 of the 67 Pts. Recurrence Score results were generated in all 67 Pts. The risk classification of the MammaPrint and Oncotype DX tests in the 57 patients where both results were available is presented in the Table below. Of note, there were only 2 high Recurrence Score results compared with 22 high risk MammaPrint results. Furthermore, 45% of the Pts with high risk MammaPrint result had a low Recurrence Score result; they also had high quantitative ER expression of more than 9.5 expression units by RT-PCR, which is associated with likely hormonal therapy benefit. There was no clear association between tumor characteristics and MammaPrint failure or differences in risk classification.
Conclusions: This direct comparison demonstrates that the MammaPrint and Oncotype DX tests classify a large proportion of Pts differently. Of note, nearly half of the Pts with high risk MammaPrint result had a low Recurrence Score indicating minimal, if any, benefit from chemotherapy.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-03.
Abstract P6-07-12: Akt2 expression is associated with good long-term prognosis in estrogen receptor positive breast cancer
Authors: Fohlin H , Pérez-Tenorio G , Fornander T , Skoog L , Nordenskjöld B , Carstensen J , Stål O 
Published: August 2014

Abstract
Introduction: Akt is a signaling modulator for many cellular processes, including metabolism, cell proliferation, cell survival and cell growth. Three isoforms of Akt have been identified, but only a few studies have concerned the isoform-specific roles in the prognosis of breast cancer patients. The aim of this study was to investigate the prognostic value of Akt1 and Akt2 in estrogen receptor positive (ER+) and estrogen receptor negative (ER−) breast cancer with long-term follow-up.
Material and Methods: The expression of Akt in tumor tissue was analyzed with immunohistochemistry in a cohort of 272 postmenopausal patients with stage II breast cancer. Hazard ratios and 95% confidence intervals were estimated using the Cox's proportional hazards model.
Results: The risk of distant recurrence was reduced for patients with ER+ tumors expressing Akt2 compared to patients with no Akt2 expression (HR = 0.49, 95% CI 0.29–0.82, p = 0.007). When adjusting for important clinical tumor characteristics and treatment, Akt2 was still an independent prognostic factor (HR = 0.38, 95% CI 0.21–0.68, p = 0.001) and the association remained long-term. After more than five years since diagnosis the risk reduction was 57% for patients with Akt2 positive tumors. The prognostic value of Akt2 increased with higher estrogen receptor levels from no effect among patients with ER− tumors to 68% risk reduction for the group with high ER-levels (P for trend= 0.042). Akt1 showed no significant prognostic information.

Conclusion: Our results indicate that Akt2 expression is associated with a lower distant recurrence rate for patients with ER+ tumors and that this association remains long-term. The prognostic value of Akt2 increases with higher estrogen receptor expression, motivating further mechanistic studies on the role of Akt2 in ER+ breast cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-12.
Abstract P6-07-23: Proportion of invasive micropapillary carcinoma lesion and primary breast cancer prognosis
Authors: Takei J , Nakayama K , Yagata H , Hayashi N , Yoshida A , Ohde S , Suzuki K , Nakamura S , Yamauchi H 
Published: August 2014

Abstract
Background: Invasive micropapillary carcinoma (IMPC) has been classified as a special type of breast cancer and has a high incidence of lymph node metastases and lymphatic invasion with poor prognosis. IMPC is often mixed with other histological types. This study examined whether the prognosis is correlated with proportion of the IMPC.
Methods: The subjects included 124 patients with IMPC that were surgically resected at St. Luke's International Hospital between February 2000 and January 2011. The resected specimens were reviewed histopathologically to determine the proportion of IMPC lesion. Patients were classified into two groups based on three cut-points of the proportion of IMPC lesion, 25%, 50%, and 75%. For each of these dichotomous classifications, we examined overall survival (OS), recurrence rate (RR) and pathological histology between the two groups. We used the Kaplan-Meier curve method and log-rank test to evaluate overall and disease-free survival time and the chi-squared test for pathological histology.
Results: The subjects were 124 cases, and two of them were male breast cancer.
The patient's age at presentation ranged from 29 to 83 years (mean 54.5 years).
At a median follow-up of 52 months (interquartile range, 7 to 115 months).
For all cut off points, there was no significant difference in survival rate and recurrence rate. We observed high-rates of lymphatic invasion and lymph node metastasis even in patients with a low proportion of IMPC lesion.
Conclusion: Our results provide no evidence to support a relationship between proportion of IMPC lesion and breast cancer prognosis. However, lymphatic invasion and lymph node metastasis was a high frequency with low proportion of the IMPC.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-23.
Abstract P6-07-29: Independent prognostic value of age depends on breast cancer subtype
Authors: Brouckaert O , Salihi R , Laenen A , Vanderhaegen J , Amant F , Leunen K , Smeets A , Berteloot P , Van Limbergen E , Weltens C , Moerman P , Peeters S , Paridaens R , Floris G , Wildiers H , Vergote I , Christiaens M-R , Neven P 
Published: August 2014

Abstract
Background: Whether age is an independent prognostic factor in early breast cancer remains controversial. Different cut-off values have been suggested in different studies and few studies assessed its value in triple negative breast cancer and other phenotypes.
Methods: We included all primary operable breast cancer patients from our prospectively managed database in UZ Leuven, Belgium. We excluded male patients, patients treated elsewhere first, patients treated with primary systemic treatment first. We assessed the effect of age as a continuous and categorical variable for distant metastasis free interval (DMFI), locoregional free interval (LRRFI) and breast cancer specific survival (BCSS) in multivariable analysis (correcting for phenotype, tumor size, nodal status, chemo−, endocrine−, radiotherapy, type of breast and axillary surgery). We assessed the effect of age for DMFI, LRRFI and BCSS in basal-like breast cancer and other phenotypes.
Results: We included 4318 patients with a mean/median age of 58/ 57 years (1170 patients were younger than 50 years) and with a median follow-up of 6,0 years. Multivariate analysis confirmed age as an independent prognostic variable for LLRFI (HR1.91; 95% CL:1.33–2.74; p = 0.0005), DMFI (HR:1.77; 95% CL:1.33–2.36; P &lt; 0.0001) and BCSS (HR:2.35; 95% CL:1.66–2.74; P &lt; 0.0001). The optimal cut-off value is 41years for LLRFI and BCSS and 44 years for DMFI. We did not find an independent prognostic value for age in triple negative breast cancer regarding DMFI and LRRFI. Results for other subtypes are subject to currently ongoing analyses.
Conclusions: Overall, young age in primary operable breast cancer patients is an independent prognostic value for DMFI, LRRFI and BCSS after adjusting for known prognostic factors. In triple negative breast cancer, age did not retain independent prognostic value for DMFI and LRRFI.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-29.
Abstract P6-07-34: Disease-related outcomes with adjuvant chemotherapy in HER2 positive or triple negative T1a/bN0 breast cancers
Authors: Shao T , Olszewski AJ , Boolbol SK , Migdady Y , Boachie-Adjei K , Sakr BJ , Klein P , Sikov W 
Published: August 2014

Abstract
Background: Previous studies reported higher relapse rates in T1a/bN0 breast cancers characterized by high-risk biology (HER2 positive or triple negative). The benefits of adjuvant chemotherapy in this group have not been evaluated. The purpose of our study was to determine potential impact of chemotherapy on incidence of relapses and to define the population appropriate for treatment based on observational data.
Methods: We pooled data from two multi-institutional databases spanning the period of 1996–2008 (Beth Israel Medical Center) and 2000–2010 (Brown University). We fitted a propensity score model to adjust for unbalanced confounders between the groups treated or untreated with adjuvant chemotherapy and, in case of HER2+ disease, with trastuzumab. Competing risk analysis was employed to study the effect of chemotherapy on cancer relapses in the matched population.
Results: The study included 321 patients (160 from Beth Israel and 161 from Brown) with a median age of 57 years (range 28–88). 111 (35%) cases were triple negative (TN) and 210 (65%) were HER2+ (of which 64% were ER+). 41% patients received adjuvant chemotherapy and 22% of HER2+ cases received trastuzumab. The treated group differed from untreated with regards to distribution of age, menopausal status, year of diagnosis, histological subtype and grade, tumor size, rates of mastectomy, and adjuvant endocrine therapy. All confounders were successfully balanced with the propensity score analysis. With a median follow-up of 56 months, 20 relapses (12 locoregional and 8 distant) and 10 unrelated deaths occurred. The cumulative incidence of relapse at 5 years was 7.3% (95% CI, 4.3–11.4) and relapse-free survival was 90.2% (95% CI, 85.2–93.6). Age less then 35 years (46.4% vs. 6.1%, p = 0.0004) and TN status (12.9% for TN versus 4.8% for HER2+, p = 0.03) were associated with higher risk of relapse. No significant differences with regards to tumor size (T1a or T1b), surgery type and other variables were observed. There was no significant effect of chemotherapy on incidence of relapse (Hazard ratio 1.2, 95% CI 0.34–4.23, p = 0.78), relapse-free survival or distant recurrence-free interval after propensity score adjustment. Additionally in the HER2+ patients, no benefit of trastuzumab was detected (hazard ratio 0.78, 95% CI 0.06–9.85, p = 0.85). Adjuvant endocrine therapy was associated with lower risk of relapse in the ER+ subgroup (p = 0.04).
Conclusion: Survival outcomes in very early stage breast cancer are excellent with current therapy even in biologically aggressive subtypes. Triple negative status and very young age correlate with higher incidence of relapse. While adjuvant endocrine therapy may be effective in ER positive subset, the risk/benefit ratio of chemotherapy with or without trastuzumab remains uncertain.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-34.
Abstract P6-07-36: A Prognostic Model For Triple-Negative Breast Cancer Patients Based On Node Status, Cathpesin-D And Ki-67
Authors: Huang L , Liu Yb , Chen S , Zhou Rj , Liu Y , Shao Z-M 
Published: August 2014

Abstract
Background: Triple-negative breast cancer (TNBC) had been classified as a breast cancer subgroup that is negative for ER, PR and HER2. The purpose of this study was to identify prognostic factors affecting outcome in women with TNBC and to construct a prognostic model which can predict recurrence.
Material and methods: We retrospectively analyzed the clinicopathologic characteristics and outcome of 284 patients diagnosed with a stage I to III triple negative breast cancer in Shanghai Cancer Hospital, including age, menopausal status, tumor size, node status, grade, ER, PR, HER-2, Cathpesin-D, PS2, Nm23, P53, Bax, Bcl-2, P27, Topo-IIa, GSTn, MDR, Cyclin D1 and Ki67. 196 patients in 2000, 2001 and 2002 belonged to training set. Prognostic significance of factors was assessed using univariate and multivariate analyses, which were combined to build a model. DFS and OS were estimated by the Kaplan-Meier method and compared among groups via the log-rank test. The prognostic value of the model was further validated in separate testing set containing 88 patients in 2003 and 2004. The median age of patients was 50 years (range, 23–85 years). 95.1% patients received cytotoxic chemotherapy after surgery; 216 (76.1%) with anthracycline based, 54 (19.0%) with CMF regimen.
Results: The median follow-up duration was 70.6 months, 102 patients (35.9%) experienced recurrence or metastasis. In Cox regression, ≥4 lymph node metastasis (HR = 3.7, P &lt; 0.001), Cath-D positive (HR = 2.1, p = 0.034), and Ki-67 index≥20%, (HR = 2.0, p = 0.006) were identified as independent factors for DFS, only ≥4 lymph node metastasis (HR = 4.9, P &lt; 0.001) showed prognostic significance for OS. The prognostic model is based on the sum total of factors, in which ≥4+ nodes, Cath-D + or Ki-67 index≥20% would contribute 1 point separately to the risk score. According to the prognostic score, patients were assigned to low-risk group(0 and 1 point) and high-risk group(2 and 3 point). The 5-year DFS rates in two groups were 82.3% and 47.8%, respectively (p &lt; 0.001). The model provided a high predictive accuracy of recurrence, which showed an AUC of 0.71 in the training set and an AUC of 0.70 in validation set.
Conclusion: Based on nodal status, Ki-67 and Cathpesin-D, we built a model that had considerable clinical value in predicting recurrence in TNBC patients, which help clinicians guide the appropriate level of adjuvant treatment and scheduling of surveillance visits.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-36.