bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-05-04: Quantification of Intra-Tumoral Heterogeneity for HER2 Gene Amplification by FISH with Proposed New (“High-ICR”) Reporting System
Authors: Schmidt RA , Dintzis SM , Allison KH. 
Published: April 2011

Abstract
Background: Current recommendations for reporting Her2 amplification by FISH have several problems, including imperfect concordance between different reporting methods, presence of an ‘equivocal’ category that is clinically problematic, and lack of accommodation for the common presence of intratumoral heterogeneity (ITH). Using a large dataset, we sought to better define ITH and develop a FISH reporting system that is more useful for patient management.
Materials and Methods: We analyzed HER2 and CEP17 counts in 32,116 individual tumor cells from 1329 consecutive breast cancer cases. Based on the individual tumor cell ratios (ICRs) and the overall average case ratios, cases were divided into three groups to explore the significance of ITH. These groups were as follows: 1) Uniformly non-amplified cases defined as &lt; 5% of individual cells with a HER2:CEP17 ratio &gt; 2.2 and an overall average case ratio &lt; 1.8 (n=763). 2) Uniformly amplified cases defined as
&gt; 90% of individual cells with a HER2:CEP17 ratio &gt; 2.2 and the overall average case ratio &gt; 2.2 (n=137). 3) Non-uniformly amplified defined as between 5-90% of cells with ratio &gt; 2.2. (n=429). The Her2:CEP17 ratios for individual cells were then compared between groups to identify the ICRs characteristic of uniformly amplified cancers.
Results: ITH for HER2 gene amplification is very common and is present in non-amplified, equivocal and amplified cases by traditional reporting criteria. Cells with Her2:CEP17 ratios &gt;= 4 are characteristic of uniformly amplified cases, are essentially absent in uniformly non-amplified cases and represent only 5.3% of cells in non-uniformly amplified cases (as defined above). Lower ratios are not characteristic of uniformly amplified cancers. Using an individual cell ratio &gt;= 4 to define significantly amplified (“High-
ICR”) cells, the following diagnostic categories are proposed: uniformly amplified (defined as having &gt;90% High-ICR cells), uniformly non-amplified (&lt;10% High-ICR cells and heterogeneous with X% amplified cells (10-90% of High-ICR cells). The distribution of cases using this proposed reporting system versus the classic CAP/ASCO categories is shown in the below table.
Proposed ITH reporting system vs classic CAP/ASCO categories
Discussion: Intratumoral heterogeneity for HER2 gene amplification is common in amplified, non-amplified and equivocal cases by current reporting guidelines but not all heterogeneity is likely to be clinically significant. The High-ICR scoring system categorizes cases based on the number of cells with significant amplification, eliminates the problematic equivocal category. and directly reports the fraction of cells that are presumed to be most amenable to treatment. We propose that the High-ICR reporting system be further validated and adopted for clinical use.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-05-04.
Abstract P6-05-06: Clinical Presentation of Molecular Apocrine Subgroup of Breast Cancer: A Rather Aggressive Group of Tumor
Authors: Hamy AS , Leman S , Barritault M , Lehmann-Che J , Abuellelah H , Giacchetti S , Cuvier C , de Roquancourt A , Bertheau P , de The H , Marty M , Espie M. 
Published: April 2011

Abstract
Background: Estrogen receptor negative (ER-) breast cancer represents 30% of breast cancers. This heterogeneous group comprises at least the basal and HER2+ subgroups. Recent data, as well as our own, has observed that the HER2+ subtype is highly heterogeneous. Several teams have identified a new “apocrine” molecular subgroup of cancer, characterized by androgen receptor (AR) expresion in an ER-context. Here, we have retrospectively identified, based on a transcriptionnal signature, these apocrine molecular tumours and described their clinical presentation and evolution.
Material and Methods:
We retrospectively identified 60 patients treated in St Louis Hospital (Paris) from 1995 to 2008 and presenting the signature of the molecular apocrine subgroup (ERA-, AR+, FOXA1+) by Q-RT-PCR.
Results:
Mean age at diagnosis was 53,5 y.o. Tumours size were T2 or more in 78% cases. Histological types were ductal invasive with intraductal component (n=22), histological apocrine (n=3), and paget disease (n=4). Tumor grade was 3 in 68%, and 2 in 21%, with lymphovascular invasion in 37%. Excluding patients receiving neo-adjuvant chemotherapy, lymph node status was negative in 41%, and positive in 52% (1 to 3, 32%, more than 4N+, 20%). By immunohistochemistry 97.4% were PR-and 58.72% overexpressed HER2.
Surgery was conservative in 46%, and 48% patients underwent mastectomy. Sixteen patients received neoadjuvant chemotherapy (27%), 41 received adjuvant chemotherapy (68%), 16 received hormonal therapy (27%), and
16 received trastuzumab (27%). With a median follow up of 60 months, 34 events (local recurrence n=9, contralateral n=3, distant metastasis n=22), and 13 deaths occurred. Median disease free survival was 48 months.
Discussion:
In this cohort of apocrine molecular carcinomas, tumor phenotypes appears to be rather aggressive, with a high proportion of poor prognosis factors (grade SBR3, lymphovascular invasion, node involvement), and are generally well-correlated to a poor clinical outcome in this population that received heterogeneous treatments. Further data are needed to precisely characterise this particular breast cancer subtype, notably patients who are not eligible to Herceptin-based regimen.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-05-06.
Abstract P6-06-01: Relationship between Vitamin D Deficiency and Breast Cancer Histology: A Retrospective Database Review
Authors: Weinstock C , Zhu Y , Bao T , Buras RR , Hanna NN , Tkaczuk K , Chumsri S. 
Published: April 2011

Abstract
Background: Vitamin D deficiency has recently been shown to be correlated with high rates of developing breast cancer (Chen P et al, Breast Cancer Res Treat; Oct 2009). However, the association between the degree of vitamin D deficiency and specific histological subtypes of breast cancer remains unclear. Preclinical data has suggested that vitamin D plays an essential role in the terminal differentiation of breast cancer cells, and thus vitamin D deficiency would be associated with the pathogenesis of estrogen receptor negative tumors (Welsh J et al, Journal of Steroid Biochem Mol Biol; Feb 2003), in particular triple-negative tumors, which are associated with a particularly aggressive clinical course. Methods: Beginning in July 2008, the majority of newly diagnosed breast cancer patients at University of Maryland Greenebaum Cancer Center had Vitamin D 25-OH levels testedon initial presentation to the clinic. We conducted a retrospective chart review to obtain information about tumor histology and vitamin D levels in these patients. Results: We include data on 71 patients who presented with newly-diagnosed breast carcinoma or DCIS between June 2008 and December 2009. Average age at diagnosis was 57 (range 36-87), and 58% of patients were African American. Stage distribution of the cohort included; DCIS-3%, stage I-15%, stage II-41%, stage III-28%, and stage IV-10%. Overall, 80% of the patients were vitamin D deficient at diagnosis, with vitamin D levels under 30 ng/ml, and 57% had levels under 20 ng/ml. Patients with triple-negative tumors were the most likely to be vitamin D deficient at diagnosis (90%) compared to hormone receptor-positive patients (75%), and they had the lowest mean and median vitamin D levels compared to all other patients.
Percentage of patients with Vitamin D deficiency
Vitamin D level by histological subtype
Hormone receptor-positive patients were significantly more likely to have normal vitamin D levels at diagnosis and significantly less likely to have severe deficiency (level &lt;10 ng/ml) than those with hormone receptor-negative tumors (p=0.037). African-American women in this cohort were also more likely to be severely vitamin D deficient, with levels &lt;10 ng/ml, than were Caucasian women (34% vs. 7%, p=0.048). Conclusion: Vitamin D deficiency is common among patients with newly-diagnosed breast cancer. Patients with triple-negative tumors may have a higher likelihood of being vitamin D deficient than patients with other histological subtypes.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-06-01.
Abstract P6-06-04: Preliminary Studies Characterizing the Prevalence of Mouse Mammary Tumor-Like Sequences in Human Tissues of Pakistani Origin
Authors: Amir S , Bilal S , Ahmed W , Zahid M , Mustafa F. 
Published: April 2011

Abstract
Background: Pakistan has the second highest rate of breast cancer in Asia after Israel with nearly 1 out of 9 women at risk of developing breast cancer at some stage in their lifetime. A potential role of viruses in human breast cancer induction/development is increasingly coming to surface. Several different groups around the world have demonstrated the presence of mousemammary tumor virus (MMTV)-like sequences in tumor but not normal breast tissue. However, these findings are controversial and seem to differ depending upon the geographic location and ethnicity of a population. Some find MMTV-like sequences in tumors of breast cancer patients only, while others believe these results are due to PCR contamination. Yet others believe that these sequences are real and represent endogenous retroviruses that reside within the human genome.
Methods: These possibilities were tested by collecting blood and breast tissue samples from breast cancer and normal individuals after informed consent and ethical approval. A total of 146 blood and tumor samples from cancer patients and 164 blood genomic DNA samples from healthy individuals were collected and subjected to PCR. Primers for different regions of the virus were designed in such a manner that they encompassed regions conserved among different MMTV strains, but were different at their 3’ ends from the human endogenous virus K (HERV-K) that has -50% homology to MMTV.
Results: Single PCR screening of all samples gave sporadic, mostly weak positive results. However, nested PCR of a subset of the samples from normal and cancer patients revealed that for the pol region, over 50-100% of the samples were positive, for env 15-75% of the samples were positive, while for long terminal repeat (LTR) 5-100% of the samples were positive, depending upon whether they were from blood or breast tissue. Sequencing of the PCR fragments further revealed these sequences to be 90-100% homologous to Mtv-8 but not HERV-K, thus identifying these amplified bands to be of MMTV origin. Finally, test of the wild Pakistani Mus musculus revealed that they contain endogenous MMTVs very similar to Mtv-8.
Conclusions: Together, these unexpected results suggest that the Pakistani population may be exposed to MMTV, maybe through zoonotic transmission from mice. These observations need further stringent study and confirmation. Differential expression studies are in the process as well as hunt for viral integration sites. It is only with a positive demonstration of integration sites in normal individuals that one can definitively prove whether MMTV is actually in the human population.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-06-04.
Abstract P6-07-01: CCN3 Impairs Osteoblasts and Stimulates Osteoclast Differentiation To Favor Breast Cancer Metastasis to Bone
Authors: Amir E , Ouellet V , Mourskaia A , Tiedemann K , Fong J , Tran-Tanh D , Clemons M , Perbal B , Komorova S , Siegel PM. 
Published: April 2011

Abstract
Background: The mechanisms underlying the osteotropism of breast cancer are not fully understood. Breast cancer cell lines that aggressively metastasize to bone appear to have increased expression of CCN3 (Nov) compared to those that weakly metastasize to bone. This study aimed to functionally implicate CCN3 in the process of breast cancer metastasis to bone.
Methods: Primary cultures of mouse bone marrow cells were used to assess the effect of recombinant CCN3 protein on RANKL, OPG and on osteoblasts and osteoclasts. To extend data obtained from cell and animal-based models, we have examined CCN3 expression a panel of human breast cancer bone metastases.
Results: CCN3 protein impaired osteoblast differentiation in a dose dependant manner, resulting in an increase in the RANKL/OPG ratio that indirectly favors osteoclast formation. CCN3 also directly induced osteoclast differentiation of RANKL-primer RAW 264.7 monocytes. CCN3 enhanced osteoclast differentiation through its ability to induce calcium mobilization and the subsequent nuclear translocation of NFATc1, a transcription factor essential for osteoclast differentiation. Immunohistochemical staining indicated that CCN3 is readily detectable, both in the breast tumor/stroma and in the majority of breast cancer bone metastasis samples.
Conclusion: Our data support a clinically relevant and important role for CCN3 in modulating the differentiation capacity of bone resident cells to support osteoclast formation and the formation of osteolytic bone metastases.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-07-01.
Abstract P6-08-04: AP-1 Activation and a Functional SNP242 Regulate the LY-6K Gene Expression in Human Breast Cancer Cells
Authors: Kong HK , Park JH 
Published: April 2011

Abstract
Background: Lymphocyte antigen 6 complex locus K(LY-6K), a member of cancer-testis antigen, is a novel breast cancer biomarker. Elevated LY-6K induces cell invasion and metastasis through activating the Raf-1/MEK/ERK signaling pathway. And in a previous study, breast cancer patients have single nucleotide polymorphism (SNP) within promoter of LY-6K. However, the molecular mechanisms that mediate regulation of human LY-6K gene expression are completely unknown. Material and Methods: The human breast carcinoma cells used in these studies include the MCF7 and adriamycin resistant MCF7. Within the pGL3 reporter vector, the -3050/+182 bp fragment and truncated fragment (deleted from -500 to -1 bp and from -1550 to -1050 bp) upstream of the LY-6K gene was subcloned and measured promoter activity. Next, multiple cis elements were identified using several gene tool software (TFSEARCH, TRANSFAC, PROMO and MATCHTM) in the promoter of human LY-6K gene. Substitution of two base pair of transcription factor binding site or single base pair of SNP was subcloned within pGL3 vector using site-directed mutagenesis and measured transcriptional activity. Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA) and supershift assays were used to demonstrate in vitro interactions between the transcription factor and transcription factor binding site within the promoter of LY-6K.
Results: We found that a novel AP-1 binding site in the LY-6K promoter. The substitution from C to G at the 242 nucleotide position in the promoter region is a functional LY-6K single nucleotide polymorphism (called SNP242), which increase AP-1 transcription binding affinity to LY-6K promoter. Ongoing studies are investigating to identify the relationship between LY-6K transcription and SNP756 which located at the 756 nucleotide position within LY-6K promoter and to find binding partner of LY-6K. We are also manipulating LY-6K transgenic mouse and knock-out mouse to investigate the mechanism of LY-6K in vivo. Discussion: The activity of the AP-1 transcription factor plays an important role in cell mobility of breast cancer cells via the promoting of LY-6K gene expression. LY-6K expression is dependent on not AP-1 transcription factor, but also SNP242 G allele by increasing AP-1 binding affinity. We demonstrated that metastasis of breast cancer cells depend on LY-6K expression turn on ERK signaling. These results suggested that LY-6K SNP242 G allele increases the risk of cancer and metastasis and LY-6K communicate with integrin-GPCR to cell migration via activating Ras/ERK signaling pathway.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-08-04.
Abstract P6-08-13: Alteration of REDD-1 Mediated mTOR Pathway and HIF-1σ Regulation in Human Breast Cancer
Authors: Lee S , Koo JS. 
Published: April 2011

Abstract
A hypoxia-related protein, REDD1 (regulated in development and DNA damage response 1), inhibits the mammalian target of rapamycin (mTOR) signaling pathway in normal cells under hypoxic condition, but a loss of REDD1 causes tumorigenesis in certain tumor cells. The purpose of this study is to investigate REDD 1 -mediated regulation of the mTOR pathway in breast cancer. Tissue microarray included samples from 224 patients with breast cancer, and 30 patients with papilloma were used as control group. The immunohistochemistry (IHC) such as estrogen receptor (ER), progesterone receptor (PR), HER-2, epithelial growth factor receptor (EGFR), cytokeratin (CK) 5/6, Glut-1, HIF-1α, REDD 1, AMPK ≥1, 14-3-3 σ, PTEN, phospho-Akt, phospho-mTOR, phospho-S6, and Ki-67 were performed. Phenotypic classification of breast cancer was performed based on the results of IHC for ER, PR, and HER-2 and fluorescent in Situ Hybridization (FISH) for HER-2: luminal A, luminal B, HER-2 overexpression, and triple negative breast cancer (TNBC). Glut-1and HIF-1 alpha were more highly expressed in TNBC, HER-2 overexpressiontype, and papilloma than luminal A and B (P = 0.000). REDD1 expression was higher in papilloma than breast cancer (P = 0.000), but no difference was found among the 4 breast cancer phenotypes (P = 0.307). HIF-1α expression was an important factor of decreased time to disease free survival and overall survival in univariate analysis (P = 0.003, and 0.000, respectively) and multivariate Cox analysis (P = 0.018, odd ratio: 7.6, and P = 0.002, odd ratio: 13.7, respectively). Among human breast cancer phenotypes, HER-2 overexpression and TNBC type demonstrated down-regulation of REDD1 under hypoxic tumor environment. In HER-2 overexpression and TNBC type, tumor cell proliferation and survival in hypoxic tumor environment could be possible due to dysinhibition of the mTOR pathway and HIF-1α stabilization through down-regulation of REDD1.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-08-13.
Abstract P6-09-02: Risk of Breast Cancer Associated with Hormone Replacement Therapy Use Differs by Age, Race, and Breast Density
Authors: Hong S , Wang W , Huo D , Siddique J , Dignam JJ. 
Published: April 2011

Abstract
Background: Observational studies and randomized trials have demonstrated an association between hormone replacement therapy (HRT) use and increased risk for breast cancer. However, this risk may vary by age and other factors, including breast density and race/ethnicity. Using data from the Breast Cancer Surveillance Consortium (BCSC), we investigate whether self-reported HRT use in the peri-menopausal and immediate post-menopausal age groups is associated with breast cancer, and also whether risk associated with HRT use differs by breast density and race. Subjects and Methods: The BCSC is a longitudinal registry of mammography screening in seven U.S. centers. In the breast cancer risk prediction model developed by Barlow et al (J Natl Cancer Inst 2006 98:1204-14), HRT use and ten other features were identified as risk factorsfor breast cancer. Data for our study consists of 1,642,824 screens and 9,300 breast cancers among the post-menopausal women aged &gt; 44 in this cohort. Logistic regression models were used to estimate odds ratios for breast cancer associated with HRT use within race, age, and density strata, adjusting for other variables from the Barlow model. Multiple imputation methods were used to accommodate missing data for HRT (14%) and other predictors.
Results: Breast cancer risk for HRT use varied by age, with no risk excess among women aged 45-49 and risk excess of 20% or greater for women aged 50-64 (Table 1). Women &gt;64 had a smaller excess risk with HRT use. There was no significant excess risk at any age for Black women, while White women age 50-64 had &gt; 20% excess risk for HRT use. White women with higher breast density had increased risk with HRT use, while Black women did not.
Table 1: Odds ratios (95% confidence interval) for HRT use (yes/no)
Conclusions: In this large cohort of mammography-screened women, HRT use did not increase breast cancer risk in the peri-menopausal period (age 45-49). Women with low breast density had smaller risk increments associated with HRT than those with high density. For Black women, increased breast cancer risk due to HRT was not apparent at any age or breast density category.
Data collection for the BCSC was supported by a NCI-funded Breast Cancer Surveillance Consortium co-operative agreement (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040).

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-09-02.
Abstract P6-09-03: No Increased Breast Cancer Risk with Hormone Replacement Therapy (HRT) in Women with Benign Breast Disease
Authors: McKian KP , Frost MH , Maloney SD , Vierkant RA , Visscher DW , Hartmann LC. 
Published: April 2011

Abstract
The association between hormone replacement therapy (HRT) and breast cancer risk in women with benign breast disease (BBD) is unclear. However, others have shown that HRT use is associated with the development of proliferative breast disease (Rohan et. al, CEBP 2008). To better clarify potential risks associated with postmenopausal hormone use in women with BBD, we performed a nested case control study within the Mayo Clinic Benign Breast Disease Cohort. In the cohort, there are 11,079 women who had benign breast biopsies between 1967 and 1996 and for whom we have outcome and risk factor data, including use of HRT. We studied 947 cases (breast cancer after BBD) and two controls matched to each case based on age and year of BBD. Information on use of HRT was obtained through use of questionnaires and medical record review with a mean time of follow up of 17.4 years. HRT use, histology, involution status, and family history were all evaluated for impact on breast cancer risk in a multivariate model.
As shown in Table 1, when looking at effects of histology, involution, and family history, we confirmed previously reported findings of risk (Hartmann LC et. al, NEJM 2005). Specifically, we saw increased risk in women with AH vs. PDWA or NP, decreased risk with complete involution vs. partial or no involution, and increased risk with strong family history vs. weak or no family history.
Associations of hormone replacement therapy and other relevant clinical variables with risk of breast cancer
Multivariate model simultaneously including all variables listed in the table. HRT=hormone replacement therapy. NP=non-proliferative. PDWA=proliferative disease without atypia. AH=atypical hyperplasia
We found that women who had used HRT had no higher risk of developing breast cancer than women who had not used HRT. Specifically, with Never Users as the reference group, those with 5 years or less exposure had OR 0.80 (0.56-1.15); 6-10 years, 0.85 (0.56-1.28) and 11+ years, 0.51 (0.36-0.72), p =0.002.
In conclusion, we found that HRT use among postmenopausal women with BBD was not associated with an increased risk of breast cancer. In this case-control set, we confirmed previous findings regarding well established risk factors of histology, involution status, and family history. While HRT use may contribute to the development of proliferative breast disease, we do not see that HRT is associated with additional breast cancer risk, beyond that of the proliferative disease itself.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-09-03.