bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Promoter Hypermethylation in Tumors and Matched Affected Lymph Nodes of Breast Cancer Patients.
Authors: Van der Auwera I. , Renard I. , Van den Eynden G. , Limame R. , Trinh X. , van Dam P. , Van Marck E. , Van Laere S. , Vermeulen P. , Dirix L. 
Published: December 2010

Abstract
Gene promoter hypermethylation plays a pivotal role in breast carcinogenesis and breast cancer progression. In this study, we investigated 6 gene promoters (RASSF1A, HIN-1, RARβ2, TWIST, CCND2 and APC) for aberrant DNA methylation by real-time methylation-specific PCR in primary tumors and matched affected lymph nodes from 30 patients with breast cancer. These data were used to explore associations between gene promoter hypermethylation and clinicopathological features, including tumor cell proliferation, angiogenesis and hypoxia marker expression.Overall, gene promoter methylation levels (ratios of DNA copy numbers for methylated and reference genes) were higher in primary tumors than in matched lymph nodes. Notably, we found significant correlations between methylation levels in primary tumors and matched lymph nodes for 5 of 6 genes (P&lt;0.05). An identical gene promoter methylation status (high or low according to the median methylation level) in primary tumors and matched lymph nodes was observed in 67% to 83% of cases. No significant associations between risk factors and gene promoter hypermethylation of the 6 genes was observed, except for the degree of spreading into nearby lymph nodes, which associated with high RASSF1A methylation levels in tumors (P=0.020) and high CCDN2 methylation levels in lymph nodes, and for HER2 expression, which was most frequently observed in tumors with low HIN-1 methylation levels (P=0.039). HIN-1 methylation levels in tumors negatively correlated with the fractions of proliferating tumor and endothelial cells determined by CD34/Ki-67 immunohistochemistry in both primary tumors (r=-0.594, P=0.001 and r=-0.619, P&lt;0.001) and in lymph nodes (r=-0.412, P=0.024 and r=-0.400, P=0.029). Furthermore, high HIN-1 methylation levels in primary tumors tended to associate with breast tumors lacking expression of the hypoxia marker carbonic anhydrase IX in tumor cells (P=0.063) and associated stroma (P=0.086). CCND2 methylation levels in affected lymph nodes positively correlated with the ratios of the fractions of proliferating tumor cells to the fractions of proliferating endothelial cells observed in both primary tumors (r=0.418, P=0.002) and in lymph nodes (r=0.563, P=0.002).In summary, gene promoter hypermethylation in primary breast tumors and matched lymph nodes are highly correlated. Further studies with larger numbers of samples are necessary to investigate the prognostic or predictive potential of these observations. For two genes, HIN-1 and CCDN2, we observed correlations between gene promoter methylation levels and tumor cell proliferation. HIN-1 and CCDN2 are frequently lost in breast cancer and are both involved in cell cycle regulation. The biological significance of these findings needs to be further explored.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1149.
Gene-Set Enrichment Analysis (GSEA) of Microarray Data in Patients with HER2-Positive Breast Cancer Treated with Preoperative Chemotherapy Including Trastuzumab.
Authors: Shimizu C. , Shimizu C. , Mogushi K. , Tamura K. , Koizumi F. , Ando M. , Kinoshita T. , Tanaka H. , Fujiawara Y. 
Published: December 2010

Abstract
Background: Identification of molecular predictors of response is important in the aspect of personalization of treatment, especially in the era of molecular targeted drugs. Genome-wide analysis such as microarray may be useful in exploring genes related to mechanism of action or resistance to trastuzumab-based treatment.Patients and Methods: 17 HER2-negative and 13 HER2-positve patients with primary breast cancer were enrolled onto this prospective study. HER2 status was determined by HercepTest (3+) or (2+) with gene amplification. The patients were prospectively treated with preoperative chemotherapy (4 cycles of 5FU/epirubicin/cyclophosphamide 500/100/500 mg/m2, q3w, followed by 12 cycles of weekly paclitaxel 80mg/m2. All HER2-positve patients were administered trastuzumab 2mg/kg weekly with paclitaxel. Gene expressions were measured using Affimetrix GeneChip Human Genome U133 Plus 2.0 array in mRNA samples extracted from pretreatment core-needle biopsy specimens. GSEA (www.broad.mit.edu/gsea/msigdb/) were performed to explore gene sets differentially expressed between tumors that achieved pathological complete response (pCR) and those did not (non-pCR). 386 gene sets corresponding to human chromosome and 1454 gene sets named by gene ontology term were examined.Results: The 5 gene sets significantly differentiated HER2-positive and HER2-negative tumors with nominal p-value of &lt;.03 and false-discovery rate (FDR) q-value of &lt;.25 included 3 gene sets located in 17q chromosome including 17q11, indicating the validity of the microarray experiment and GSEA in a relatively small study. Six HER2-positive tumors achieved pCR. We identified 22 and 112 gene sets with nominal p-value of &lt;0.01 and &lt;0.05 that differentiated pCR and non-pCR in HER2-positive tumors, respectively. The top 22 gene sets included gene sets related to regulation of phosphorylation, receptor complex, cell proliferation, cytoplasmic vesicle, regulation of apoptosis and immune response. Other significant gene sets were those related to cell adhesion, signal transduction, cell proliferation and protein homodimerization. We could not identify gene sets which was differentiately expressed in tumors with pCR and non-pCR with FDR q-value of &lt;.25 probablely because of the sample size.Conclusion: Although the results are still exploratory, GSEA seems to be helpful in narrowing down the gene sets from wide range of pathways in molecular network even in a small study if the selected gene sets are biologicaly robust.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1167.
Outcomes of Women Who Were Premenopausal at Diagnosis of Early Stage Breast Cancer in the NCIC CTG MA17 Trial.
Authors: Goss P. , Ingle J. , Martino S. , Robert N. , Muss H. , Shepherd L. , Pritchard K. , Livingston R. , Davidson N. , Perez E. , Cameron D. , Whelan T. , Palmer M. , Tu D. 
Published: December 2010

Abstract
Background: MA17 showed that adjuvant letrozole after 5 years of tamoxifen markedly reduced the risk of recurrence in women with ER+ early stage breast cancer and improved overall survival in women presenting with node +ve disease. Most trials of early adjuvant aromatase inhibitor therapy required women to be postmenopausal at diagnosis to be eligible. We report here on a subset of women in the MA17 trial who were premenopausal at initial diagnosis and in whom subsequent menopause, prior to randomization, may have influenced their outcome on extended adjuvant letrozole.Methods: Women randomized to MA17 were divided into 2 groups: 1) pre-menopausal (&lt; 50 years of age but underwent bilateral oophorectomy at time when tamoxifen treatment started or &lt; 50 years of age at the start of tamoxifen treatment but became amenorrheic during adjuvant chemotherapy or tamoxifen treatment) and 2) post-menopausal. Disease-free survival (DFS) from time of randomization for women in these two groups were summarized by Kaplan-Meier curves and compared based on log-rank test and Cox model.Results: 889 women were identified as premenopausal and 4,277 as postmenopausal. Treatment, age, race, duration of tamoxifen, prior adjuvant chemotherapy, and mastectomy were independently associated with menopausal status on multivariate analysis. The interaction between treatment and menopausal status was statistically significant for DFS (p=0.02), indicating that women diagnosed with pre-menopausal breast cancer had significantly greater benefit (Hazard ratio=0.25, 95% CI: 0.12-0.51) with letrozole treatment in terms of DFS than those with post-menopausal status (hazard ratio=0.69 with 95% CI from 0.52 to 0.91). In comparison with women treated with placebo, pre-menopausal women on letrozole had a significantly higher incidence of arthralgia (24 vs. 16%; p=0.004) but a lower incidence of vaginal bleeding (10 vs. 16%; p=0.01). Compared with placebo post-menopausal women receiving letrozole had a higher incidence of hot flashes/flashes (55 vs. 50%; p=0.001), arthralgia (25 vs. 21%; p=0.002), myalgia (15 vs. 12%; p=0.007) and alopecia (5 vs. 3%; p=0.003).Conclusions: Letrozole after tamoxifen was more effective in improving DFS in women who were premenopausal at primary diagnosis than those who were postmenopausal. Letrozole was well tolerated in premenopausal women. These data indicate that women who are premenopausal at the time of diagnosis but become postmenopausal anytime before, or during, adjuvant tamoxifen should be considered for extended adjuvant therapy with letrozole.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 13.
Progesterone Receptor (PR) Promoter Methylation – Role as a Predictive and Prognostic Marker in Breast Cancer.
Authors: Pathiraja T. , Jelinek J. , He R. , Shetty P. , Hartmaier R. , Margossian A. , Hilsenbeck S. , Issa J. , Oesterreich S. 
Published: December 2010

Abstract
Estrogen receptor α expression is a well known and clinically utilized predictor of endocrine treatment response. In addition, loss of expression of the progesterone receptor (PR), an estrogen induced gene, has been shown to be associated with resistance to endocrine therapy. PR is known to be epigenetically regulated by DNA methylation, but only a few studies have correlated PR DNA methylation with its expression in breast cancer. Previous studies are contradictory and have been limited by small sample size. There is also evidence that differential expression of the two PR isoforms, PRA and PRB, might contribute to breast tumorigenesis, and altered hormone response. Whether PRA and/or PRB DNA methylation could predict response to endocrine therapy remains an open question. Further, there are no published studies so far testing whether PRA and/or PRB methylation have prognostic significance.Our objective was 1) to determine whether there was an association between PRA and/or PRB methylation levels with total PR expression in breast tumors, and 2) to determine if PRA and/or PRB methylation would have predictive and/or prognostic value. For this study, we utilized tumor DNA from patients with ER-positive breast tumors which were treated with adjuvant tamoxifen after surgery (n=500), and from patients treated with surgery only (n=500). PR expression was determined by ligand binding assay, and PRA and PRB promoter methylation was measured by bisulfite pyrosequencing.Both PRA and PRB methylation were significantly (p&lt;0.0001) associated with PR expression, in an inverse relationship. Low PR expression was significantly (p=0.02) associated with worse overall survival (OS), and there was a trend towards shorter disease free survival (DFS) in the tamoxifen treated group. There was no association between PR expression and survival in the untreated group. PRA methylation was significantly (p&lt;0.0001) associated with PRB methylation. Intriguingly, increased PRA methylation was significantly associated with shorter DFS (p=0.047) and OS (p=0.0067) in tamoxifen treated patients, and with shorter OS (p=0.008) in the untreated patients. In contrast, there was no significant association between PRB methylation and survival in either tamoxifen treated or untreated patients.Our results show that PR expression is significantly associated with PR methylation. The data suggest that PRA methylation is a predictive marker for tamoxifen response and also a prognostic marker for breast cancer progression. This is the largest study so far to elucidate the association of PRA and PRB methylation with PR status, response to tamoxifen, and tumor prognosis, and we believe that it provides useful insights into the role of PR methylation in breast tumorigenesis.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2002.
Delay in Treatment Does Not Predict Outcome in Inflammatory Breast Cancer.
Authors: Levine P. , Schenfeld J. , Hoffman H. , Young H. 
Published: December 2010

Abstract
Aim: Inflammatory breast cancer (IBC) is an extremely aggressive form of breast cancer that fortunately has proven to be increasingly controlled by modern multimodal chemotherapy. Many doctors consider the immediate use of chemotherapy as critical to the outcome, and delays in treatment due to diagnostic issues have on occasion led to law suits. One such law suit led us to examine the relative importance of delay in diagnosis and other potential prognostic factors in a series of well documented IBC patients.Methods: 134 patients reported to the North American IBC Registry were evaluated for prognostic factors related to disease outcome. Relevant information included the time intervals between onset of symptoms and first medical visit, first medical visit to onset of chemotherapy, and progression free survival (PFS). Other parameters included initial response to chemotherapy, cell surface receptors and extent of disease at diagnosis. Patients were categorized according to the extent of clinical breast involvement and the presence or absence of dermal lymphatic invasion (DLI).Results: Patients with a delay of diagnosis of 60 days or less had a mean PFS of 4.41 years (N=62) while those with a delay &gt;60 days had a mean PFS of 4.58 years (N=58). Initial response to chemotherapy was an important predictor of outcome: 31 patients with a complete clinical response had a median PFS of 5.12 years vs. 4.38 years for 71 patients that had a partial clinical response and 4.01 years for 15 patients with no significant response or progression of disease. The detection of dermal lymphatic invasion (RR: 2.77; 95%CI: 1.4-5.46) and clinical metastases at diagnosis (RR 2.81. 95% CI:1.16-6.80) were also significantly associated with a poorer outcome. The presence or absence of hormone receptors and HER2-neu markers were not predictive of outcome.Conclusion: Delay in initiating chemotherapy was not a significant factor in determining outcome of IBC. Initial extent of disease and response to chemotherapy were the two most imnportant factors in predicitng outcome of treated patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2012.
Steroid Receptor RNA Activator Protein (SRAP): A Potential New Prognostic Marker for Estrogen Receptor-Positive/Node-Negative/Younger Breast Cancer Patients.
Authors: Yan Y. , Yan Y. , Skliris G. , Skliris G. , Penner C. , Chooniedass-Kothari S. , Chooniedass-Kothari S. , Cooper C. , Nugent Z. , Fristenski A. , Hamedani M. , Blanchard A. , Myal Y. , Murphy L. , Murphy L. , Leygue E. , Leygue E. 
Published: December 2010

Abstract
Purpose: The steroid receptor RNA activator (SRA) is a functional RNA suspected to participate in the mechanisms underlying breast tumor progression. This RNA is also able to encode for a protein, SRAP, whose exact function remains to be determined. Our aim was to assess, in a large breast cancer cohort, whether levels of this protein could be associated with outcome or established clinical parameters.Experimental Design: Following antibody validation, we have assessed SRAP expression by tissue-microarray (TMA) analysis of 372 tumors with known steroid receptor and node status. Clinical follow-up was available for all the corresponding patients. Immunohistochemical scores were independently determined by two investigators and averaged. Statistical analyses were performed using standard univariate and multivariate tests.Results: SRAP levels were significantly (Mann-Whitney rank sum test, P&lt;0.05) higher in estrogen receptor-alpha positive (ER+, n = 273), in progesterone receptor positive (PR+, n= 256) and in older patients (age ≥ 65 years, n = 183). When considering ER+ tumors, PR+ tumors, or young patients (&lt; 65 years), patients with high SRAP expression had a significantly (Mantel-Cox test, P &lt; 0.05) worse breast cancer specific survival (BCSS) than patients with low SRAP levels. SRAP also appeared as a very powerful indicator of poor prognostic for BCSS in the subset of ER+, node negative and young breast cancer patients (Cox regression analysis, n = 60, BCSS Hazard Ratio=13.937, P&lt;0.0001).Conclusion: Our data suggest that SRAP might be a new predictor of breast cancer specific survival in younger breast cancer patients with ER+/node negative tumors.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2017.
The 76-Gene Signature Defines High-Risk Patients That Benefit from Adjuvant Tamoxifen Therapy.
Authors: Zhang Y. , Sieuwerts A. , McGreevy M. , Graham C. , Cufer T. , Paradiso A. , Harbeck N. , Span P. , Hicks D. , Crowe J. , Tubbs R. , Thomas B. , Lyons J. , Sweep F. , Schmitt M. , Schittulli F. , Golouh R. , Talantov D. , Wang Y. , Foekens J. 
Published: December 2010

Abstract
Background: A significant proportion of ER-positive tumors exhibit resistance to endocrine therapy. Clinical studies in LNN/ER+ patients show that the absolute distant disease-free survival benefit of tamoxifen therapy is only about 9%, with a relative benefit of about 30%. These benefits from treatment may, however, differ substantially according to e.g. patient's age and the tumor level of ER and it is therefore of importance to identify biomarkers that allow identification of those breast cancer patients who may actually benefit from adjuvant tamoxifen. This study was to assess the benefit from adjuvant systemic tamoxifen therapy in breast cancer risk groups identified by the previously established prognostic 76-gene signature.Material and Methods: In 300 lymph node-negative (LNN) estrogen receptor-positive (ER+) breast cancer patients (136 treated with adjuvant tamoxifen, 164 having received no systemic adjuvant therapy), distant metastasis-free survival (DMFS) as a function of the 76-gene signature was determined in a multicenter fashion.Results: In 136 tamoxifen-treated patients, the 76-gene signature identified a group of patients with a poor prognosis (hazard ratio (HR), 4.62, P = 0.0248). These patients showed a 12.3% absolute benefit of tamoxifen in 10-year DMFS (HR, 0.52, P = 0.0318) compared with untreated high-risk patients. This represented a 71% increase in relative benefit compared with the 7.2% absolute benefit observed for all 300 patients without using the gene signature. In the low-risk group there was no significant 10-year DMFS benefit of tamoxifen.Discussion: In summary, the 76-gene signature defines high-risk patients who benefit from adjuvant tamoxifen therapy. Although we did not study the value of chemotherapy in this study, low-risk patients identified by the 76-gene signature have a prognosis good enough that chemotherapy would be difficult to justify. The prognosis of these patients is sufficiently good, in fact, that a disease-free benefit for tamoxifen therapy is difficult to prove, though benefits in terms of oco-regional relapse and a reduction in risk for contralateral breast cancer might justify ormonal therapy in these patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2021.
Biopsy Confirmation of Metastatic Disease in Breast Cancer: Results from a Large Prospective Study.
Authors: Amir E. , Freedman O. , Simmons C. , Miller N. , Geddie W. , Dranitsaris G. , Maung H. , Napolskikh J. , Lax M. , Clemons M. 
Published: December 2010

Abstract
Purpose: Decisions about systemic treatment of women with metastatic breast cancer are often based on estrogen receptor (ER), progesterone receptor (PgR), and HER2/neu status of the primary tumour. This study prospectively investigated concordance in receptor status between primary tumour and distant metastases at various stages of progression and assessed the impact of any discordance on patient management.Methods: Biopsies of suspected metastatic lesions were obtained from patients and analyzed for ER/PgR and HER2/neu. Receptor status of metastases was compared to the primary tumour. The treating physician completed questionnaires before and after biopsy to determine whether the biopsy result lead to a change in treatment plan.Results: One hundred and sixteen women were enrolled and 102 underwent biopsy. Of these 52 (51%) were newly diagnosed with metastatic disease, 17 (17%) had received one line of metastatic treatment and 35 (34%) had received 2 or more lines of treatment in the metastatic setting. 86/102 (84%) of samples were sufficient analysis; of these 5/86 biopsies (6%) showed benign disease and one biopsy (1%) confirmed a different malignancy (indolent lymphoma). Changes in hormone receptor status were observed in 33%. Among these, ER discordance was seen in 11%, PgR discordance in 27% and discordance in both ER and PgR in 5%. Loss of PgR was the most common change in hormone receptor status (25%). HER2/neu showed 4% discordance. Three patients (3%) gained and one patient (1%) lost HER2/neu expression. Biopsy results led to a change of management in 12% of patients. Patients with newly diagnosed metastatic disease were more likely to show discordance than those previously treated in the metastatic setting. Among triple negative primary tumours, no changes in receptor expression of metastases were seen.Conclusions: This is the largest prospective biopsy study we are aware of. Results demonstrate the presence of substantial discordance in receptor status between primary tumour and metastases. The number needed to biopsy to alter immediate management was 8.5, although biopsy information could also be useful in planning subsequent treatments. Tissue confirmation should therefore, be considered in all patients with suspicion of metastatic recurrence or progression.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2023.