bluuebunny/crossref_metadata_2025_split huggingface dataset:
P2-05-04: Mapping the Specific Gene Families Activated in the Lymphangiogenesis and Vasculogenic Mimicry Exhibited by Inflammatory Breast Cancer.
Authors: Liu H , Luo AZ , Mu Z , Chu K , Ye Z , Alpaugh RK , Fernandez S , Boley KM , Jin J , Wright MC , Cristofanilli M , Robertson FM 
Published: June 2012

Abstract
Background: Inflammatory breast cancer (IBC) is the most metastatic variant of locally advanced breast cancer. Although IBC is diagnosed less commonly than other types of breast cancer, it is extremely aggressive, and accounts for a disproportionate number of breast cancer related deaths annually. IBC exhibits very specific patterns of lymphangiogenesis and vasculogenic mimicry, however detailed studies of the genes and proteins involved in these angiogenic processes are lacking. This study performed whole unbiased gene transcription studies with validation by protein arrays using all available pre-clinical cell lines and in vivo xenograft models of IBC, including a new model of IBC, FC-IBC01, which exhibits lymphovascular invasion, to identify the specific pathways involved in the distinctive angiogenesis observed in IBC.
Materials and Methods: Real-time quantitative RT-PCR, cDNA microarray gene profiling, immunofluorescence with confocal imaging and protein arrays were used to examine differential expression of specific angiogenic gene families including VEGFA,B,C,D, VEGF Receptor genes, and ANG/TIE genes linked to angiogenesis and lymphangiogenesis.
Results: Activity of the matrix metalloproteinase, MMP-2, is required for IBC tumor cells to undergo vasculogenic mimicry (VM), which is associated with a loss of TIMP-2, a well known inhibitor of angiogenesis. Therapeutics that target MMP activity can successfully inhibit this VM. Furthermore, pre-clinical models of IBC that form IBC tumor emboli exhibit lymphovascular invasion that is associated with distinct patterns of expression of genes that encode for distinct receptor tyrosine kinases that may represent important therapeutic targets for IBC.
Discussion: Identification of the distinct angiogenic pathways that are activated in IBC provides insight into the therapeutic targets that may abrogate the distinct lymphovascular invasion and vasculogenic mimicry that are linked to the aggressive metastasis of IBC.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-05-04.
P2-06-01: Genomic Instability in Breast Cancers from Atomic Bomb Survivors: An Analysis of Microarray-Comparative Genomic Hybridization with Old Archival Tissues.
Authors: Oikawa M , Yoshiura K-I , Kondo H , Miura S , Kurashige T , Nagayasu T , Yano H , Nakashima M 
Published: June 2012

Abstract
Background: Sixty-six years after two atomic bombs (A-bombs) explosion on Hiroshima and Nagasaki, the incidence of breast cancer in A-bomb survivors still higher than that in controlled populations. We have reported a higher incidence of HER2 and C-MYC oncogene amplification in breast cancers from A-bomb survivors, which suggested genomic instability (GIN) induced by A-bomb radiation exposure might promote breast carcinogenesis in A-bomb survivors. The purpose of this study was to clarify the effect of A-bomb radiation exposure on GIN in breast cancer using microarray-comparative genomic hybridization (aCGH).
Materials and Methods: DNA was extracted from the paraffin-embedded tissues of invasive ductal cancers from 11 survivors exposed at 1.5km from the hypocenter and 9 calendar year-matched non-exposed patients followed by aCGH analysis using a high-density oligonucleotide microarray (Agilent® SurePrint G3 8×60k microarray). The total length of chromosomal aberrant region was used as an indicator of GIN, and correlation with clinicopathological factors were statistically tested.
Results: The mean of the derivative log ratio spread (DLRSpread), which estimates the log ratio noise by calculating the spread of log ratio differences between consecutive probes along all chromosomes, was 0.60 (range, 0.30 to 1.05). The concordance of aCGH results with FISH results for HER2 gene amplification was 90%. Samples from A-bomb survivors had significantly more copy number aberrations (CNA) than samples from control patients (P= 0.040). Samples with C-MYC gene amplification determined by aCGH analysis tended to harbor more CNA (P= 0.20), and age at the time of diagnosis tended to be inversely associated with the total length of chromosomal aberrant regions (P= 0.13). The multivariate analysis with covariance revealed that the status of A-bomb exposure was the only independent factor which was significantly associated the total length of chromosomal aberrant regions (P= 0.0324).
Conclusions: This study suggested that A-bomb radiation may affect the development of chromosomal aberrant regions including oncogene amplification by inducing GIN and may be associated with a higher histological grade in breast cancer found in A-bomb survivors.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-06-01.
P2-06-04: Phosphatidylinositol-3-Kinase Pathway Mutations Are Common in Breast Columnar Cell Lesions.
Authors: Troxell ML , Brunner AL , Montgomery K , Zhu SX , Neff T , Warrick A , Beadling C , Corless CL , West RB 
Published: June 2012

Abstract
The phosphatidylinositol-3-kinase pathway is one of the most commonly mutated in invasive breast carcinoma, with PIK3CA mutations present in ∼25% of invasive carcinomas, and AKT1 mutations identified in up to 5%. Several studies have demonstrated the same complement of mutations in ductal carcinoma in-situ (DCIS), as well as benign papillomas. We sought to investigate whether PIK3CA mutations occur in breast columnar cell lesions (CCL).
Twenty-five breast resection specimens containing CCL (including columnar cell change, columnar cell hyperplasia, and flat epithelial atypia) were identified from the files of Stanford University Pathology; 15 of these had associated invasive carcinoma (IDC) or carcinoma in situ. DNA was prepared from punches of formalin-fixed paraffin-embedded tissue blocks using standard methods. DNA extracts were screened for a panel of point mutations using a multiplex PCR panel with a mass-spectroscopy readout (Sequenom MassARRAY). The panel covers 321 mutations in 30 genes, including ABL, AKT1/2/3, BRAF, CDK4, CTNNB1, EGFR1, ERBB2, FBX4, FBXW7, FGFR1/2/3, FLT3, GNAQ, HRAS, JAK2, KIT, KRAS, MAPK2K1/2, MET, NRAS, PDGFRA, PIK3CA, PTPN11, RET, SOS1, and TP53. The majority of mutations were confirmed by Sanger sequencing. PIK3CA mutations were identified in 12/25 CCL (48%); paired normal breast tissue was tested in 21 cases and was negative for mutations in all but one case. In associated DCIS, 4/8 (50%) harbored PIK3CA mutations, while 3/9 IDC had mutations (33%, 2 PIK3CA, 1 AKT1). The mutation status of CCL and carcinomas was frequently discordant. Of 15 cases, only 6 demonstrated the same genotype in matched samples of CCL and carcinoma (5 wildtype, 1 PIK3CA H1047R). Interestingly, 5 patients had mutations in CCL with wildtype DCIS or IDC; 2 patients had different point mutations in CCL and carcinoma, including one patient with discordant mutant DCIS and wildtype IDC. Only 3 cases had wildtype CCL and mutated carcinoma.
The nearly 50% PIK3CA mutation prevalence in CCL is greater than reported in most studies of invasive breast cancer. Further, CCL and carcinoma were frequently discordant for PIK3CA/AKT1 mutation status; most commonly the CCL harbored a PIK3CA mutation, while the associated carcinoma was wildtype. Although these findings need validation in a larger study, they raise interesting questions as to the role of PIK3CA/AKT pathway in breast carcinogenesis, and as to the biologic/precursor potential of CCL.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-06-04.
P2-09-11: Role of 18FDG-PET/CT in the Staging of Large Primary Operable Breast Cancer.
Authors: Groheux D , Giacchetti S , Hamy A-S , Vercellino L , Delord M , Berenger N , Toubert M-E , Misset J-L , Hindié E , Espié M 
Published: June 2012

Abstract
Background: Prospective evaluation of the role of 18FDG-PET/CT in patients with large primary operable breast cancer.
Material and Methods: During 56 months, consecutive patients with large (&gt;2cm) breast cancer and clinical stage IIA/IIB/IIIA (based on clinical examination, mammography, breast MRI and ultrasonography) underwent 18FDG-PET/CT. The nuclear physician was blind to the results of any other procedure (bone scan, chest X-ray, liver ultrasound, or thoraco-abdominal CT scan). Results: Out of the 131 examined patients, 36 had clinical stage IIA (34 T2 N0, 2 T1 N1), 48 stage IIB (20 T3 N0, 28 T2 N1), and 47 stage IIIA (29 T3 N1, 9 T2 N2, 9 T3 N2). 18FDG-PET/CT modified staging for 5.6% of stage IIA patients, for 14.6% of stage IIB patients, and for 27.6% of stage IIIA patients. However, within stage IIIA, the yield was specifically high among the 18 patients with N2 disease (56% stage modification). When considering stage IIB and primary operable IIIA (T3 N1) together, the yield of 18FDG-PET/CT was 13% (10/77); extra-axillary regional lymph nodes were detected in 5 and distant metastases in 7 patients. In this series, 18FDG-PET/CT outperformed bone scan with only 1 misclassification versus 8 for bone scan (p=0.036).
Discussion: 18FDG-PET/CT provided useful information in 13% of patients with T3 N0 / T2 N1 / T3 N1 disease. The yield was more modest in patients with T2 N0 disease. The very high yield in the case of lymph nodes classified N2 demonstrates that stage IIIA comprises two quite distinct groups of patients.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-11.
P2-11-05: Stromal Matrix Metalloproteinase-14 Expression Correlates with the Grade and Biological Behavior of Mammary Phyllodes Tumors.
Authors: Lee JS , Park MH , Yoon JH 
Published: June 2012

Abstract
Phyllodes tumors (PTs) of the breast are rare biphasic tumors with the potential for invasion and metastatic spread. Matrix metalloproteases (MMPs) and their tissue inhibitors of metalloproteases (TIMPs) are involved in several key aspects of tumoral growth, invasion and metastasis, but little is known of their expression in PTs. The objective of this study was to assess the expression of MMPs and TIMPs in PTs and to determine their association with grade and clinical behavior of PTs. Eighty-two PTs (50 benign, 22 borderline, and 10 malignant) were studied. Automated immunohistochemical staining for MMP-1, -2, -7, -9, -11, -13, and -14 and TIMP-1, -2, and -3 was performed using tissue microarray blocks and the expression of MMPs and TIMPs was assessed in both the stromal components. There were no significant differences in the expression of stromal MMPs and TIMPs in the three groups of PTs, except for MMP-14. There was a significant increase in stromal MMP-14 expression with increasing PT grade (P &lt; 0.01). The stromal MMP-14 expression in the borderline and malignant PTs was higher than that in benign PTs (P &lt; 0.05 and P &lt; 0.05, respectively). Furthermore, the expression of stromal MMP-14 was associated with a higher rate of recurrence (P &lt; 0.05). Our results show for the first time that stromal MMP-14 expression is associated with the grade and clinical behavior of PTs of the breast.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-11-05.
P2-11-10: Low Toll-Like Receptor 9 Expression Is Required for the Aggressive Behavior of Triple Negative Breast Cancer Cells in Hypoxia.
Authors: Selander KS , Tuomela J , Sandholm J , Karihtala P , Pressey C , Ilvesaro J , Vuopala K , Kauppila JH , Kauppila S , Harris KW , Graves D , Jukkola-Vuorinen A 
Published: June 2012

Abstract
Toll-like receptor-9 (TLR9) is a cellular DNA-receptor and a member of the innate immune system which is widely expressed in breast cancers. Although synthetic TLR9-ligands stimulate breast cancer cell invasion in vitro, through down-regulation of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), the role of this protein in breast or other cancer pathophysiology is unclear. We discovered that low tumor TLR9 expression is associated with a significantly shortened breast cancer specific survival among patients with triple negative tumors, but not among those with ER+ tumors. We further discovered that hypoxia induces TLR9 expression in breast cancer cells in vitro and in vivo. Although the triple negative TLR9 siRNA MDA-MB-231 breast cancer cells (with lower TLR9 expression) were less invasive than control siRNA cells in normoxia, these cells became highly aggressive in hypoxia and they formed significantly larger tumors than corresponding control cells in an orthotopic model in vivo. Further in vitro experiments revealed that the removal of TLR9 expression through siRNA significantly potentiated the hypoxia-induced invasive capacity of the triple negative MDA-MB-231 cells, but not that of the ER+ T47-D cells. Low TLR9 expression in hypoxia resulted also in complete disappearance of TIMP-3 in the MDA-MB-231 cells, but not in the ER+ T47-D cells. Taken together, these studies suggest that low TLR9 expression has different effects on the behavior of triple negative and ER+ breast cancer cells in hypoxia; triple negative cells become more invasive under these conditions, possibly through loss of endogenous invasion inhibitors, such as TIMP-3. Furthermore, these studies suggest that low TLR9 expression in triple negative breast cancers may serve as a novel prognostic factor and help characterize the group of patients that are at a high risk of relapse. Finally, our results suggest that any treatments or factors that lower TLR9 expression or induce hypoxia in residual or metastatic triple negative breast cancer cells, might actually induce their spread.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-11-10.
P2-12-11: Clinical Relevance of a IL-8/B-Cell Gene Signature Identified from Triple Negative Breast Cancer (TNBC) in Intrinsic Breast Cancer Subtypes.
Authors: Rody A , Holtrich U , Ruckhaeberle E , Radosa J , Juhasz-Boess I , Solomayer EF , Kaufmann M , Karn T 
Published: June 2012

Abstract
Background: As presented recently (SABCS 2010, #S5-5) a ratio of high B-cell and low IL-8 metagenes using gene expression analysis identified 32 % of triple negative breast cancers with good prognosis and was the only significant predictor in multivariate analysis including routine clinicopathological variables.
However, the clinical relevance of this signature within the intrinsic breast cancer subtypes still remains unclear and is analyzed here.
Methods: Affymetrix gene expression data from n=2417 breast cancer patients have been assembled. We performed an unsupervised analysis to define metagenes that distinguish molecular subsets within TNBC (SABCS 2010, #S5-5). A high expression of B- cell metagenes was associated with good and high expression of IL-8-related metagenes were associated with poor prognosis.
To identify intrinsic subtypes we used the method previously described by Hu et al. (2006) and the prognostic value within those subtypes was assessed by analyzing the event free survival of patients as function of high and low B-cell/IL-8 metagene ratio.
Results: Comparing ER positive with ER negative patients the B-ceh7LL-8 ratio showed only in ER negative breast cancer a significant prognostic value (log rank p-value &lt;.0001).
Within the entire cohort 37.8 % of patients could be assigend to luminal A, 35.2 % to luminal B, 7,4 % to erbB2 and 19.6 % to basal-like subtypes. Event free survival of patients with good or poor B-cell/IL-8 ratio showed only in basal-like breast cancer patients a statistical significant difference (p&lt;.0001). However, we could not observe any difference in prognosis in luminal A and B, as well as erbB2 tumors. No difference in the expression of the proliferation metagene was observed when samples of the intrinsic subtypes were stratified according to the prognostic predictor based on high expression of the B-Cell metagene and low expression of the IL-8 metagene.
Conclusion: The B-cell/IL-8 ratio is highly prognostic in basal-like/TNBC and shows no association with proliferation status.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-11.
P2-12-18: A Prognostic Model Based on Node Status, Cathpesin-D and Ki-67 Predict the Outcome of Patients Failing To Achieve Pathological Complete Response after Anthracycline-Based Neoadjuvant Chemotherapy for Breast Cancer.
Authors: Chen S , Chen C , Yu K , Shao Z 
Published: June 2012

Abstract
Background
Aim of this study was to evaluate factors which could possibly affect the outcome of patients failing to achieve pathological complete response (pCR) after anthracycline-based neoadjuvant chemotherapy (NCT) for breast cancer, and built a prognostic model to predict disease free survival (DFS) and overall survival (OS).
Material and Methods: We retrospectively collected data of 199 stage II-III breast cancer patients who had failed to achieve pathological complete response after neoadjuvant chemotherapy in Shanghai Cancer Hospital. The NCT regimens were NE (navelbine 25mg/m2, day 1, 8 and epirubicin 60mg/m2, day 1; every three weeks) or CEF (cyclophosphamide 600 mg/m2, day 1; epirubicin 60 mg/m2, day 1 and 5-fluorouracil 600 mg/m2, day 1; every three weeks) for a median treatment course of 3 cycles. To develop the prognostic model, variables at baseline(age, menopausal status, tumor size, node status, ER, PR, and HER-2) and at surgery(tumor size, grade, histotype, node status, vascular invasion, ER, PR, HER-2, Cathpesin-D, P53, Topo-IIα, Nm-23, Bcl-2, BAX, MDR, GSTn, PS2, P27, Cyclin D1 and Ki-67) were investigated. Multivariate Cox regression model and Kaplan-Meier method was used to build the model, and show the discrimination of DFS and OS in different risk groups.
Results: By multivariate analysis, ≥4 lymph node metastasis (HR=1.9, P=0.009), Cath-D positive (HR=2.5, P=0.006), and Ki-67 index≥20% (HR=1.9, P=0.001) at surgery were independent predictors for lower DFS and OS rate among non-pCR responders. We built a prognostic scoring model on the basis of these variables, in which ≥4+ nodes, Cath-D + or Ki-67 index≥20% would contribute 1 point separately to the risk score. The 5-year DFS rates in low(0 point), intermediate-low(1 point), intermediate-high(2 points) and high risk groups(3 points) were 94%, 65%, 43%, and 28%, respectively (Log-rank teat p&lt;0.001). The 5-year OS rates in these four groups were 94%, 84%, 66% and 34%, respectively (Log-rank test p&lt;0.001).
Conclusion: Post-NCT node status, Cathpesin-D and Ki-67 were used to develop a prognostic model which could simply discriminate patients with poor prognosis among non-pCR responders after anthracycline-based neoadjuvant chemotherapy, and might help to tailor further individualized treatment strategies.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-18.
P2-12-20: Adjuvant! Online Is Overoptimistic in Predicting Survival of Asian Breast Cancer Patients.
Authors: Bhoo Pathy N , Yip CH , Hartman M , Saxena N , Taib NA , Bulgiba AM , van der Graaf Y , Verkooijen HM 
Published: June 2012

Abstract
Background
Adjuvant! Online is a free web-based tool which predicts 10-year breast cancer outcomes and efficacy of adjuvant therapy in patients with breast cancer. As its prognostic performance has only been validated in high income Caucasian populations, the model was validated in a middle income Asian setting.
Material and Methods: Within the University Malaya Hospital-Based Breast Cancer Registry, all 631 women receiving standard surgery for invasive non-metastatic breast cancer between 1993 and 2000 were identified. Calibration of Adjuvant! Online was evaluated by comparing the predicted 10-year overall survival with observed 10-year survival. Discrimination of the model was tested by receiver operating characteristic (ROC) analysis.
Results: For the entire cohort, Adjuvant! Online predicted 10 year survival (70.3%) was significantly higher than the observed 10 years survival (63.6 %) by a difference of 6.7% (95%CI: 3.0%- 10.4%). The model was especially overoptimistic in women under 40 years and in women of Malay ethnicity, where survival was overestimated by approximately 20% (95%CI: 9.8- 29.8%) and 15% (95%CI: 5.3−24.5%) respectively.

Adjuvant! Online performed fairly in terms of discrimination, with an area under ROC curve of 0.73 (95%CI: 0.69−0.77).
Conclusion: Even though Adjuvant! Online is capable of discriminating between good and poor survivors, it systematically overestimates survival. These findings suggest that the model requires adaptation prior to use in Asian settings.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-20.
P2-14-02: NCIC CTG MA.27: Clinical Tolerability and Overall Survival of Racial and Ethnic Minority Women on Aromatase Inhibitor Therapy.
Authors: Moy B , Shepherd LE , Chapman J-AW , Le Maitre A , Gelmon KA , Elliott C , Ingle JN , Goss PE 
Published: June 2012

Abstract
Background
Aromatase inhibitors (AIs) are standard adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. We previously reported that racial/ethnic minority women receiving an AI in NCIC CTG MA.17 experienced fewer hot flashes, fatigue, and arthralgias than Caucasians (Moy B et al. Ann Oncol 2006;17:1637). Here we examined whether race affected clinical outcomes in the MA.27 AI trial comparing exemestane (E) with anastrozole (A).
Methods: Fisher's exact test was used to compare observed side effects (0 vs grades 1–5) between minority and Caucasian women. Adverse events (AE), including menopausal symptoms, were assessed according to the Common Terminology Criteria of the National Cancer Institute (version 3.0). ITT univariate test of race effects on overall survival (OS) was determined with a stratified log-rank test, while multivariate testing was with stratified Cox regression.
Results: Among 7312 for whom race was known, distribution was: Caucasian (n=6939; 95%); black (n=235; 3%); Asian/Native Hawaiian/Pacific Islander (n=93); 1%; American Indian (n=39; 1%); and mixed race (n=6). Among women treated with E, minorities reported a significantly lower incidence of hot flashes (45% vs. 56%; p=0.003) and fatigue (34% vs. 46%; p=0.001) compared to Caucasians. Similarly with A, minority women reported significantly fewer hot flashes (47% vs. 58%; p=0.002) and lower cholesterol (12% vs. 18%; p=0.01); however, they reported more headaches than Caucasians (16% vs. 10%; p=0.01). Caucasian women were more likely to discontinue therapy due to AE or side effects (32% vs. 24%). There was a significant OS interaction (p=0.02) between race and treatment with minority women on E having fewer deaths than those on A. Caucasian women had HR of E to A of 0.98 (95% CI 0.81−1.20), p=0.85, while minorities had HR of E to A of 0.72 (95% CI 0.33−1.58), p=0.41.
Conclusions: Minority women tolerated AIs better and were also more compliant than Caucasians, supporting our previous findings. A significant interaction between race and type of AI therapy for OS was seen, favoring exemestane in minority women. Replication of these findings in larger cohorts is necessary. Since race/ethnicity may serve as a surrogate for genetic differences, our findings suggest pharmacogenomic differences which require further research.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-14-02.