bluuebunny/crossref_metadata_2025_split huggingface dataset:
P5-08-04: Mammographic Microcalcifications and Breast Cancer Tumorigenesis: A Radiologic-Pathologic Analysis.
Authors: Naseem M , Murray J , Hilton JF , Han D , Hogeveen S , Heersink RL , Muradali D , Simmons C , Bell D , Haq R , Brezden-Masley C 
Published: June 2012

Abstract
Background
Microcalcifications (MCs) are tiny deposits of calcium in breast soft tissue. They serve as key diagnostic radiological features for localization of malignancy. Approximately 30% of early invasive breast cancers have fine, granular MCs detectable on mammography; however, their role in breast cancer tumorigenesis is currently unknown. The purpose of this study was to investigate the relationship between mammographic MCs and breast cancer pathology.
Methods: A retrospective chart review was performed for 882 women treated for breast cancer between 2000–2010 at St. Michael's Hospital. Demographic information (age and menopausal status), tumor pathology (size, histology, grade, nodal status and lymphovascular invasion), hormonal status (ER and PR), HER-2 overexpression and presence of MCs were collected for breast cancer patients. Chi-square tests were performed for categorical variables and t-tests were performed for continuous variables. All tests were two-sided and p-values less than 0.05 were considered statistically significant.
Results: A total of 826 patient charts were included; 56 (6.4%) patients had metastatic carcinoma and were excluded from analysis. Only 37.0% (326/882) of the patients presented with mammographic MCs. Patients were more likely to have MCs if they were HER-2 positive (51%) as opposed to being HER-2 negative (33.4%) (p=0.001). There was a significant association between MCs and being perimenopausal with a mean age of 50 (65.2%) (p=0.012). Patients with invasive ductal carcinomas (39.7%) were more likely to present with MCs than were patients with other tumor histology (p=0.001). There was a positive correlation between MCs and tumor grade (p=0.051), with grade III tumors (41.85%) presenting with the most MCs, followed by grade II (37.95%) and grade I (29.8%). There was no significant association between mean age, mean tumor size, ER and PR status with the presence of MCs.
Conclusion: This is the largest study that suggests the appearance of MCs on mammograms is strongly associated with HER-2 overexpression, invasive ductal carcinoma and perimenopausal status. Since HER-2 is implicated in mediating aggressive tumor growth and metastasis, future studies should investigate the molecular pathways underlying HER-2 overexpression and MC development. This would help better understand the role of MCs in breast cancer tumorigenesis.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-08-04.
P5-10-01: Metabolic Pharmacodynamic Effect Evidenced by 18FDG-PET as a Tool for Early Prediction of Iniparib Efficacy in Metastatic Triple Negative Breast Cancer (MTNBC): A Proof of Concept Study.
Authors: Kerrou K , Gligorov J 
Published: June 2012

Abstract
Rationale: It was hypothesised that Iniparib or 4-iodo-3-nitrobenzamide acts as an irreversible inhibitor of PARP1 and possibly other enzymes. It has shown successively promising then confusing results in MTNBC in combination with chemotherapy. To date, its mechanism of action has not been completely elucidated but since 1992, inhibition of glycolysis by iniparib and subsequent necrotic cell death has been described. We hypothesised that early inhibition of glycolysis evidenced by in-vivo imaging with 2-((18)F)Fluoro-2-Deoxy-D-Glucose Positron-Emission Tomography (18FDG-PET) may be a predictor of efficacy to iniparib, as it was previously reported for other anticancer drugs.
Objectives: To detect metabolic pharmacodynamic effect of iniparib plus chemotherapy by means of 18FDG PET and proof the concept of its use as an early predicitive tool of Iniparib efficacy in MTNBC.
Patients & Methods: From March to November 2011, 8 pts were included in our institution in a randomized phase II study comparing bi-weekly versus weekly iniparib treatement in combination with gemcitanine and carboplatin. All patients had 18FDG-PET at baseline, at day 7 (D7). The maximum value of standardized uptake value (SUVmax) of all measurable metastatic lesions was measured and the median SUVmax was calculated for all patients at baseline and D7. The metabolic response was defined as the percentage of reduction of SUVmax (SUVmax Baseline — SUVmax D7) / SUVmax Baseline and the median SUVmax response was correlated to RECIST 1.1 response at six weeks and to disease-free survival (DFS).

Results: The median decrease in SUVmax of evaluable lesions measured at D7 was predictive of RECIST 1.1 response at six weeks and was correlated to the best obtained response during the treatment phase. Furthermore, it showed a linear correlation with DFS (y = −0,0007x - 0,1325; R2 = 0,3402).
Conclusion: Metabolic pharmacodynamic effect as evidenced by 18FDG PET as soon as one week of treatement act as an early predicitive tool of Iniparib plus chemotherapy efficacy in MTNBC.
Considering the lack of a predicitive biomarker of response and if confirmed on larger study, 18FDG PET could be used as a surrogate predictive biomarker is this setting. These results may be considered as an in-vivo proof of concept for the inhibition of glycolysis by iniparib.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-10-01.
P5-11-09: High Concordance for Microarray Based Determination of ER, PR and HER2 Receptor Status and Local IHC/FISH Assessment Worldwide in 749 Patients.
Authors: Wesseling J , Cusumano G , Tinterri C , Sapino A , Zanconati F , Lutke-Holzik M , Nguygen B , Deck K , Querzoli P , Perin T , Giardina C , Seitz G , Guinebretiere J , Barone J , Watanabe T 
Published: June 2012

Abstract
Background The level of estrogen receptor (ER), progesterone receptor (PR) and HER2 expression is predictive for prognosis and/or treatment response in breast cancer patients. However, differences in fixation and IHC and subjective interpretation can substantially affect the accuracy and reproducibility of the results. The commercially available TargetPrint test measures the mRNA expression level of ER, PR and HER2 and provides high quality second opinion for local IHC/FISH assessment. This study compares results from the microarray-based TargetPrint with IHC and FISH (for HER2 IHC2+) generated by local standard procedures.
Methods Prospective tumor samples were collected for 749 patients diagnosed with breast cancer stage I to IV between February 2008 and January 2011. The mRNA level of ER, PR and HER2 (TargetPrint) was assessed in the Agendia laboratories (Agendia Inc, Irvine, CA; Agendia BV, Amsterdam, the Netherlands) in fresh tumor samples submitted from 22 hospitals from Europe, New Zealand, Japan and US. The results of the IHC/FISH assessments performed according to the local standards at the hospitals were compared to the quantitative gene expression readouts.
Results Of the 749 samples, IHC assessment was unknown for 5 ER samples and 4 PR samples; FISH was unknown for 24 samples. TargetPrint read out was not assessed for HER2 for 11 samples.
Median age of these patients was 61 years. Comparison of IHC and gene expression read out by TargetPrint showed a concordance of 95% for ER; 82% for PR and 91% for HER2.
In this study, only 4% of all IHC ER positive samples were classified negative by microarray. In contrast, 14% of IHC ER negative samples were classified positive by microarray. However for HER2, 28% of IHC/FISH HER2 positive samples were classified negative by microarray and 5% of IHC/FISH HER2 negative samples were classified positive by microarray.
Samples with discordant classifications for TargetPrint and local assessment are being reviewed in greater detail by a central pathologist.
Conclusions Microarray based readout of ER, PR and HER2 status using TargetPrint is highly comparable to local IHC and FISH analysis in 749 analyzed samples in various hospitals worldwide. The results indicate mRNA expression read out for ER, PR and HER2 by TargetPrint provides high quality second opinion for local IHC/FISH assessment.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-09.
P5-11-10: Reproducibility and Robustness of the FDA Approved INFORM HER2 Dual ISH DNA Probe Cocktail Assay.
Authors: Loftin IR , McElhinny AS , Miller R , Garcia C , Bai I , Ranger-Moore J , Ostrem J , Padilla M , Grogan T 
Published: June 2012

Abstract
Background: Amplification and/or HER2 overexpression is associated with poor clinical outcome for patients with invasive breast carcinoma. Determination of HER2 status dictates eligibility of patients for trastuzumab (Herceptin) therapy, which has been shown to improve prognosis. We present data from the inter-observer reproducibility and robustness studies of the FDA approved INFORM HER2 Dual ISH DNA Probe Cocktail (HER2 Dual ISH) assay, which is an alternative to FISH. The assay is fully automated and is scored using light microscopy providing morphological context.
Methods: Ninety-five human invasive breast carcinoma specimens (a mix of amplified and non-amplified cases) were stained in a study, using the HER2 Dual ISH assay. The slides were enumerated by two qualified readers. The same cohort was stained using Path Vysion FISH and read by one qualified reader.
To verify the robustness of the HER2 Dual ISH assay, customer selectable options for factors known to impact the staining quality and intensity, which can be varied for troubleshooting, were tested on human invasive breast carcinoma cases and xenografts. The slides were evaluated by one qualified reader.
For both studies all assay steps were fully automated on a VENTANA BenchMark XT automated slide stainer using silver metallographic and red colorimetric detections for Dual ISH.
Results: In the inter-observer study the first pass staining success rate was &gt;93% for the HER2 Dual ISH assay, while the FISH first pass staining success rate was 59%. Some cases were rescued after a second attempt, which yielded a second pass staining success rate of 80% for FISH and 97% for HER2 Dual ISH. The negative, positive and overall agreement rates and 95% confidence intervals for the 61 clinical samples of this cohort that were enumerable with both FISH and the HER2 Dual ISH assay are 94.7 (75.4−99.1), 95.2 (84.2−98.7), 95.1 (86.5−98.3) and 89.5 (68.6−97.1), 97.6 (87.7−99.6), 95.1 (86.5−98.3) for reader A vs. FISH and reader B vs. FISH respectively. The positive and negative agreement rates for the inter-observer reproducibility of the HER2 Dual ISH assay were 94.7 and 97.6 %, respectively. In robustness testing, the recommended staining protocol was shown to be effective. All conditions tested resulted in appropriate staining (except for mildest cell conditioning and protease options). Conclusion: The fully automated FDA approved INFORM HER2 Dual ISH assay is robust, reproducible and concordant with the manual FISH assay in determining HER2 status in invasive breast carcinoma.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-10.
P5-13-02: Prediction of Dasatinib Sensitivity of Breast Cancer Based on a Novel Tyrosine Kinase-Activity Profiling Assay.
Authors: Kawai M , Torikoshi Y , Notoya M , Gohda K , Ueno NT , Ishihara H 
Published: June 2012

Abstract
Background: Receptor tyrosine kinases and other membrane-associated tyrosine kinases are frequently overexpressed, activated, or mutated in cancer cells and cause aberrant signal transduction, which leads to cellular proliferation, angiogenesis, metastasis, and antiapoptosis. Blockage of these signals is considered an efficient strategy in cancer therapy, and to date, several tyrosine kinase inhibitors (TKIs) and antibody drugs targeting such kinases have been developed and are routinely used in clinics. However, the efficacy rates of the drugs are, unfortunately, limited. To provide optimum care for individual patients, an accurate prediction method for drug efficacy is now strongly demanded. Recent studies have shown that alteration of multiple kinases is involved in both primary and acquired drug resistance. Advantages of multi-targeted TKIs have also been reported. These findings indicate the need for a comprehensive evaluation of multiple kinases for predicting drug response. To achieve this, we developed a novel method of comprehensively profiling kinase activity.
Materials and methods: We characterized the membranous tyrosine kinases of breast cancer cell lines using a newly established profiling assay. Briefly, crude membrane fractions were prepared and directly subjected to the assay with nonspecific substrate (Poly(Glu4-Tyr)). The profile of the kinases in the crude membrane fraction was obtained by inhibiting the total activity with 13 selected kinds of adenosine triphosphate antagonists, independently. The residual activity (RA) of membranous kinases was defined as the percentage of activity with/without TKI.
Results: Nineteen breast cancer cell lines were classified as “sensitive” (n = 6) and “resistant” (n = 13) to dasatinib according to the definition in the publication (Cancer Res., 67 2226–38. 2007). The RA of tyrosine kinases targeted by different types of TKIs was determined by our assay, and we found that two RAs (src inhibitor 1 and PP1) showed statistically significant differences between the “sensitive” and “resistant” groups (p=0.017, and p=0.002, respectively, Student's t-test). The RA of the two TKIs were also significant predictors for dasatinib sensitivity in a receiver operating characteristic curve analysis (area under the curve: 0.846 for src inhibitor 1 and 0.910 for PP1). Since the major target of dasatinib are src family kinases, protein expressions of the src family of the cell lines were quantified by a Western blotting and compared between the groups. We found that the protein expression is not a statistically significant predictor of dasatinib sensitivity.
Conclusion: We have shown that a comprehensive tyrosine kinase activity profiling assay of cancer cells can predict dasatinib sensitivity. We plan to validate this assay prospectively in patients with breast cancer who receive dasatinib.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-02.
P5-13-10: Discordance of Estrogen Receptor and HER-2/neu Status Can Be Seen between First and Subsequently Biopsied Metastatic Lesions in Breast Cancer.
Authors: Lower EE , Kennedy D 
Published: June 2012

Abstract
Background
We have previously reported discordance between primary and first metastasis for both estrogen receptor (ER) and HER-2/neu (HER 2) status (Breast Cancer Res Treat 2005;90:65–70 and Breast Cancer Res Treat 2009;113:301–6). Because biomarker status is the primary determinant for targeted therapy, changes in biomarkers can impact recommendations for systemic treatment.
Materials and Methods: In order to evaluate the possibility of further discordance with the development of additional metastatic sites, we examined the ER and HER 2 status of primary and first and subsequently biopsied breast cancer metastasis. In most cases, the subsequent site of metastasis was the second detected metastasis. Pathology reports were reviewed from 65 patients with biopsy proven first and additional metastasis; however, immunostain results were not available for all three timepoints for all patients. Sites of biopsied metastasis included lung, liver, bone, chest wall, and central nervous system.
Results: The time between the initial diagnosis and first metastasis was 102 (3-676) months [Median (Range)], and the time between the first and subsequent metastasis was 60 (6-273) months. For ER, there was discordance between the primary lesion and either the first or subsequent metastasis in 18 of 65 cases (27.7%). Discordance of the ER occurred between the first and subsequent metastasis in 12 (18%) of cases. Three patterns of ER discordance occurred in these 12 cases: 4 cases of both primary and first metastasis negative with subsequent metastasis positive; 3 cases of primary positive, first metastasis negative, and subsequent metastasis positive, and 5 cases of primary and first metastasis positive and subsequent metastasis negative. For HER 2, discordance was detected between the primary and either first or subsequent metastasis in 11 of 36 cases (30.6%). Further discordance between the first and subsequent metastatic lesions occurred in 8 of 51 (16%) of cases.
Conclusions: A significant level of discordance for either ER or HER 2 was detected between first and subsequent metastatic breast cancer lesions. For breast cancer patients with new metastasis, consideration of reevaluating ER and HER-2/neu status may be worthwhile.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-10.
P5-13-22: Gene Expression Profiles Predict Pathological Complete Response to Standard Neoadjuvant Fluorouracil, Doxorubicin, and Cyclophosphamide and Paclitaxel with or without Trastuzumab in Early Breast Cancer.
Authors: Tamura K 
Published: June 2012

Abstract
Background
To examine the feasibility of gene expression signature as a predictor of pathological complete response (pCR) to sequential fluorouracil, doxorubicin, and cyclophosphamide (FEC) and weekly paclitaxel (P) with or without trastuzumab (T) neoadjuvant chemotherapy.
Materials and Methods: We have conducted consecutive two prospective phase II, establishing training and validation sets, with similar eligible criteria include, stage IIA-IIIC, chemotherapy-naïve, measurable disease, age ≥ 20, PS 0/1, and adequate organ function. Patients were treated preoperatively with 4 cycles of FEC (500/100/500 mg/m2) followed by 12 cycles of weekly P (80 mg/m2) with or without T (2mg/kg). Patients underwent pretreatment fine-needle biopsy for cDNA microarray using Affimetrix Gene Chip U133 plus 2.0 arrays with 30,000 differential expressions of various genes. We ranked gene probes from training sets according to a predictive power concerning pCR by Wilcoxon, and validated them using validation sets by SVM.
Results: Between July 2007 and December 2010, 122 patients were enrolled in the two consecutive prospective studies (training: 89 pts, validation: 33 pts). Median age was 51. PS 0/1: 115/7; Stage IIA/IIB/IIIA/IIIB/IIIC: 30/57/20/14/1; Histological subtype: ER+HER2− (LA) / ER+HER2+ (LB) / ER-HER2− (TN) / ER-HER2+ (enrich-HER): 51/18/24/29. All patients have received curable operations. pCR rate was 31.1% (LA; 2.0%, LB; 44.4%, TN; 37.5%, enrich-HER; 69.0%). 104 (85.2%) sufficient mRNA for cDNA microarray from individual primary breast cancer tissues fine-needle biopsy are available. As reported previously, the breast cancers were classified into a Luminal A/B, Basal-like, HER2−enriched, Claudin-low intrinsic subtypes, indicating a high quality of the representative method. In HER2 positive breast cancer, HER2−enriched subtype was a reproductive predictive marker. In contrast, In HER2 negative breast cancer, three genes (N-myc and STAT interacter, Tryptophanyl-tRNA synthetase, and IQCE) and basal-like subtype were validated as the predictors of pCR. The three genes were also identified as predictors of pCR in the triple negative population.
Conclusions: Specific gene expression profiles predict pCR to standard neoadjuvant regimen, especially in triple negative breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-22.
P5-14-03: Genomic Comparison of Paired Primary Breast Carcinomas and Macrometastatic Lymph Node Metastases Using Quantitative RT-PCR by Oncotype DX: Assessment of the Recurrence Score and Quantitative Single Genes.
Authors: Boolbol SK , Kirstein L , Harshan M , Klein P , Cohen J-M , Chadha M , Baehner FL , Malamud SC 
Published: June 2012

Abstract
Background
NCCN guidelines now include consideration of the 21 gene RT-PCR assay in node negative, hormone sensitive breast cancers greater than 0.6 cm. Recent data suggests a potential role for testing of node positive(N1), hormone sensitive patients as well. Currently, no data exists on testing of metastatic lymph nodes. We sought to establish the feasibility of Oncotype DX® testing in the metastatic lymph nodes and, furthermore, to evaluate the genomic concordance between the primary tumor and the nodal deposit. These results may further our understanding of tumor heterogeneity and biological selectivity in the process of lymph node metastasis and ultimately systemic metastases.
Methods: We examined the formalin fixed paraffin embedded tumor tissues (FPET) from 100 breast cancer patients from our institution's pathology database with available paired primary tumor and macrometastic nodal deposits by Oncotype Dx® testing. Inclusion criteria included patients with macrometastatic lymph node disease, hormone receptor positive, HER2 negative primary breast cancer. The testing laboratory was blinded from the clinical outcomes data available on these patients. All FPET samples had H&E slides made which were reviewed by board certified surgical breast pathologists to determine if there was sufficient invasive tumor and to direct dissection of all lymph node samples. The Recurrence Scores and quantitative single gene values from the paired samples will be examined descriptively with scatterplots and Pearson correlation coefficients and reported at the meeting.
Results: All 100 paired specimens were sent for Oncotype DX testing. 24 samples were found during standard H&E review to not have sufficient tumor for the assay. Of the 176 samples created for RNA extraction 173 samples had sufficient RNA for the Oncotype DX assay: 85 lymph node and 88 primary breast carcinoma samples. Recurrence Scores and quantitative single gene values from the paired primary breast carcinoma and lymph node samples will be examined descriptively and reported at the meeting.
Conclusion: Previous comparisons of paired primary and metastatic samples have used immunohistochemistry and FISH which are susceptible to variability in preanalytic variability such as delay to fixation, choice of fixative and duration in fixative. This study, using quantitative RT-PCR, will be one of the largest comparisons of tumor biology in paired samples yet reported in the era of genomic subtyping and may have implications for systemic adjuvant treatment.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-03.