bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-01-07: Evaluation of FLT PET-CT as an imaging biomarker of proliferation in primary breast cancer
Authors: Woolf DK , Beresford M , Li SP , Sanghera B , Wong WL , Amin V , Ah-See M-L , Miles D , Sonoda L , Detre S , Dowsett M , Makris A 
Published: August 2014

Abstract
Background
[18F]flurothymidine (FLT) is proposed as an positron emission tomography (PET) imaging biomarker of proliferation for breast cancer. The aim of this prospective study was to assess the feasibility of FLT PET-CT as a technique for predicting response to neoadjuvant chemotherapy (NAC) in operable breast cancer and to compare baseline FLT to Ki-67.
Methods
20 patients with primary breast cancer were recruited into this study and 19 received NAC with FEC (n = 6) or FEC-T (n = 13). A baseline FLT PET-CT scan was performed and repeated before the second cycle of chemotherapy. Expression of Ki-67 in the diagnostic biopsy was quantified after being stained by Dako Ki67 MIB-1 antibody and% positive cells scored. From the FLT PET-CT scans standardized uptake value maximum (SUVmax) were calculated.
Results
All 20 patients completed the baseline scan and 17 completed the second scan. Baseline Ki-67 results were available for 19 patients. Median age was 52 years (range 32 to 67), 12 patients were ER/ PR +ve, 6 Her-2 +ve and 6 triple negative.
Mean baseline SUVmax was 7.3 (range 2.92 to 13.87) and 4.62 (range 1.79 to 14.15) post 1 cycle of NAC (range 7 to 14 days), representing a drop of 2.68 (36.3%). Mean baseline Ki-67 was 32.23 (range 2.3 to 68.4). Pearsons correlation showed a significant correlation between pre-chemotherapy Ki-67 and SUVmax of 0.604 (p = 0.006).
7 out of 17 (41%) patients achieved near pCR or pCR (pathological responders) after NAC and all of these had a reduction in SUVmax with a mean percentage value of –36.5% (range -0.5% to -62.5%). 10 out of 17 (59%) patients were non-responders and 8 of these had a reduction in SUVmax with a mean percentage value of -36.2% (range 11.3% to -70.7).
Conclusions
Baseline SUVmax measurements of FLT PET-CT were significantly related to Ki-67 suggesting that it is a proliferation biomarker. However, in this series neither the baseline value or the change in SUVmax after one cycle of NAC were able to predict response as most patients had a sizeable SUVmax reduction.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-07.
Abstract P4-04-04: Targeted resequencing of germline PTEN-negative patients with Cowden disease reveals alternate mechanism of molecular alteration
Authors: Sevenet N , Gourdon S , Lafon D , Dupiot-Chiron J , Geneste G , Jones N , Bonnet F , Longy M 
Published: August 2014

Abstract
Introduction
Cowden disease belongs to the PTEN hamartoma tumor syndrome (PHTS) group, defined by germline PTEN heterozygous inactivation. Describing the PTEN germline mutation in Cowden disease patients is of particular importance for their breast cancer and thyroid carcinoma predisposition evaluation.
Material & methods
Targeted resequencing was done on germline DNA of 22 index cases patients with a Cowden disease clinically well established since they do not demonstrate any PTEN mutation analyzed using our current screening method (EMMA, Enhanced Mismatch Mutation Analysis, similar to high resolution melting). The 565 exons of 34 genes of interest together with the entire genomic locus of PTEN were captured using the SureSelect oligonucleotide library capture (Agilent technologies). The bioinformatics resources Suredesign, Ensembl human genome v70 and a UCSC repeat masker least stringent were used to create the capture design. This gave us 28405 unique 120-mers oligonucleotide probes which were duplicated 1 to 16 times depending on the GC content or the size of the targeted regions (maximum boosting performance criteria). For each gene of interest, an exon of the surrounding gene was also captured in order to define the extent of gross gene rearrangement. Samples were prepared according the manufacturer's recommendations.
Results
Each of the 22 Cowden disease patients demonstrates a mean rate of 70 intronic mutations in the entire genomic locus of PTEN. All of those for which the minor allelic frequency is unknown, were subjected to splicing site bioinformatic prediction. For one patient, the prediction reveals the apparition of a splicing site in a deep intronic mutation of the large intron 1 of PTEN. Furthermore, next generation sequencing (NGS) seems to be more sensitive than our current screening method since for two patients, a germline mosaic exonic heterozygous inactivating mutation of PTEN was detected and confirmed by Sanger sequencing on different biological samples. The level of mosaicism was evaluated by NGS at 3 to 12% depending on the sample and confirmed by pyrosequencing. In addition, some mutations were identified in exons of genes encoding proteins of the PI3Kinase pathway, which could be involved in disease belonging to the PHTS group. With an increasing sensitivity, NGS is a powerful tool to detect low frequency variant. This could used to explain at a molecular level Cowden disease with no initially detectable PTEN mutation. Clinical and biological rationale, bioinformatics workflow and comprehensive results will be presented.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-04.
Abstract P4-05-09: Estrogen receptor (ER) mRNA expression and molecular subtype distribution in breast cancers that are ER-negative but progesterone receptor-positive by immunohistochemistory
Authors: Iwamoto T , Matsuoka J , Nogami T , Motoki T , Shien T , Taira N , Niikura N , Hayashi N , Doihara H , Symmans WF , Pusztai L 
Published: August 2014

Abstract
Purpose: We examined Estrogen receptor (ER) mRNA expression and molecular subtypes in breast cancers that are Progesterone receptor (PR) positive but ER negative by immunohistochemistry (IHC) to assess if these cancers molecularly resemble true ER positive cancers.
Patients and Methods: Patients were those with newly diagnosed ERBB2-negative breast cancer treated with neoadjuvant chemotherapy containing sequential taxane and antheracycline-based regimens (then endocrine therapy if ER-positive by IHC). ER and PR status was determined by IHC in 501 primary breast cancers in routine pathology laboratory. Gene expression profiling was done with the Affymetrix U133A gene chip (Gene Expression Omnibus number: GSE25066). We compared expressions of ESR1, MKI67 mRNA and molecular subtypes determined by the PAM 50 classifier between IHC-ER-positive/PR-positive (n = 223), ER-positive/PR-negative (n = 73), ER-negative/PR-positive (n = 20), and ER-negative/PR-negative (n = 185) cancers. We also plotted survival curves by ER and PR status based on IHC.
Results: ER or PR positivity by IHC was defined ≥ 1% staining. ER positivity by ESR1 mRNA expression was defined as &gt; 10.18 previously published. Among the IHC-ER-negative/PR-positive, ER-positive/PR-negative, and both ER/PR-positive, and ER/PR-negative patients, 25%, 79%, 96% and 12% were positive by ESR1 mRNA expression, respectively. The average ESR1 expression was significantly higher in the ER/PR-positive and ER-positive/PR-negative cohorts compared with the ER-negative/PR-positive or ER/PR-negative cohorts. The average MKI67 mRNA expression was significantly higher in the ER-negative/PR-positive and ER/PR-negative cohorts. Among the ER-negative/PR-positive patients, 15% were luminal A, 5% were Luminal B, and 65% were basal like; among the ER-positive/PR-negative patients, 59% were luminal type. The relapse free survival rate of ER-negative/PR-positive patients was equivalent to ER/PR-positive or ER-positive/PR-negative, and significantly better than that of the ER-negative/PR-negative cohort.
Conclusion: Only 20-25% of the ER-negative/PR-positive tumors show molecular features of ER-positive cancers (i.e high ER mRNA expression and luminal molecular class). These cancers also have higher proliferation rate than ER-positive cancer. However, the survival of these cancers with only chemotherapy is similar to ER-positive cancers with chemotherapy and endocrine therapy, and is better than ER-negative cancers. The contribution of endocrine therapy to this good outcome is to be invested in the future.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-09.
Abstract P4-06-02: Changes in intrinsic subtype of breast cancer during tumor progression in same patient
Authors: Kim C , Kim A 
Published: August 2014

Abstract
Introduction: Hormone receptor(ER, PR), Epidermal growth factor receptor 2 (HER2) and Ki67 are important prognostic factors and key variables in classification of intrinsic subtype which is essential for selection of adjuvant therapy in breast cancer management. There have been previous reports that instability of hormonal and HER2 status during tumor progression. Recently breast cancer treatment guidelines recommended using intrinsic subtype for treatment option. Especially intrinsic subtypes were determined by using 4 immunohistochemical (IHC) assays that is ER (estrogen receptor), PR (progesterone receptor), HER2 and Ki67. The purpose of this study was to investigate whether the intrinsic subtype changes as tumor progresses from ductal carcinoma in situ (DCIS) to lymph node metastasis
Methods: 90 cases of breast cancer were constructed with 2-mm core tissue microarrays (TMA). All cases simultaneously have DCIS, invasive carcinoma (IDC) and lymph node metastasis. IHC and Silver in situ hybridization (SISH) assay was performed on TMA. All of the cases after 2005 had informed consent from the patients for using their medical information and tumor tissues. Evaluation of hormone receptors expression was based on the Allred scoring method. For HER2, membranous staining was evaluated according to the guidelines of the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP). Using the results of the immunohistochemical analyses, tumors were classified into four subtypes. To define luminal A type is an ER positive and/or PR positive, HER2 negative and Ki67 low. As well as luminal B type is an ER positive and/or PR positive, HER2 positive or Ki67 high. HER2 type is HER2 positive, ER negative and PR negative and Ki67 low or high. Basal like type is classified as exhibited ER, PR, and HER2 negative.
Results: Of the 90 cases, the lesions with DCIS showed 39 were luminal A, 24 were luminal B, 19 were HER2, and 8 were basal like. The lesions with IDC showed 31 with luminal A, 26 with luminal B, 23 with HER2, and 10 with basal like. Also, 28 were luminal A, 29 were luminal B, 21 were HER2, and 12 were basal like for lymph node metastasis. Overall 25% breast cancer change their intrinsic phenotype during progression.
Conclusions: This study demonstrated that a subset of breast cancers can change their intrinsic subtype during cancer progression. These changes have huge impact on patient prognosis and management because each subtype have own different optimized treatment options according to St Gallen and NCCN guideline.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-06-02.
Abstract P4-06-04: Effect of genomic heterogeneity on breast cancer progression and metastatic spread
Authors: Ellsworth RE , Valente AL , Blackburn HL , Decewicz A , Deyarmin B , Mamula K , Shriver CD , Ellsworth DL 
Published: August 2014

Abstract
Purpose: DNA fingerprinting has revealed discordant patterns of chromosomal alterations in primary breast tumors (PBT) compared to matched metastatic axillary lymph node tumors (MLNT); however, whether these genetic differences reflect the timing of dissemination of cells with metastatic potential from the primary tumor, intratumoral heterogeneity of the primary breast tumor, or independent seeding of lymph nodes with metastatic cells remains unclear.
Patients and Methods: From the 30 node-positive patients evaluated in this study, allelic imbalance (AI) data was generated using 52 microsatellite markers from 5-19 areas of each PBT as well as from available MLNT. Data were analyzed using pairwise correlations, ANOVA and PHYLIP.
Results: The frequency of genomic changes was significantly higher (P&lt;0.001) in PBT areas (13%) than MLNT (9%). No two PBT areas had identical patterns of AI and the percent concordance (PC) of AI events between tumor regions ranged from 0-65% (average 33%). Of the 196 MLNT from 28 patients, PC between MLNT from the same patient ranged from 0-88% (average = 32%). Neither the overall frequency of AI nor the PC differed significantly between sentinel (SLN) and non-SLNs. Phylogenetic analysis revealed that within patients, many MLNT appeared to be descended from different areas of the PBT, but patterns of descent were complex.
Conclusions: Both PBT and MLNT are characterized by extensive molecular heterogeneity, MLNT appear to originate from different areas of the PBT, and SLN metastases are not genomically more advanced than non-SLN metastases. These data suggest that metastatic dissemination may be influenced by both spatial and temporal factors, with cells with metastatic potential colonizing lymph nodes throughout the development of the PBT, and that SLN metastases do not appear to be a source of metastatic cells for non-SLN but rather MLNT arise by independent colonization.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-06-04.
Abstract P4-06-10: Breast cancer subtypes in Indian women: A comparison of clinicopathological features and outcome
Authors: Mane AD , Deshmukh SP , Nag SM , Guha A , Sane SP , Zade BP 
Published: August 2014

Abstract
Background:
Immunohistochemical markers are often used to classify breast cancer into different subtypes that have distinct biological behaviour. The aim of this study was to estimate the distribution of the different subtypes of breast cancer based on immunohistochemistry, in the Indian population and determine their associations with clinicopathological features and outcome.
Methods:
This is a 5 year retrospective study of 521 breast cancer patients to compare the clinicopathological features and survival of four subgroups – Luminal A (ER/PR +, Her 2 neu –), Luminal B (ER/PR +,Her 2 neu +), Her 2 enriched (ER-/PR -, Her 2 neu +)and triple negative(ER-,PR-,Her 2 neu -).
Results:
Majority (43.8%) of the patients were in luminal A subgroup. Luminal B patients were 14.8%, Her 2 enriched group were 16.1% and triple negative patients were 25.3%. Median follow up was 34 months. Patients in luminal A subgroup were more likely to be postmenopausal, have smaller size tumours, have grade I/II tumours and have better survival (OS-91.06%), though it was not statistically significantly different from other subgroups.
Clinicopathological characteristics and outcome according to breast cancer subtypes Luminal ALuminal BTriple negativeHer 2 neup valueMenopausal statusPre39.09%13.71%30.46%16.75% Post46.60%15.43%22.22%15.74%0.159Type of surgeryBCS44.25%19.54%22.99%13.22% MRM41.78%12.50%27.96%17.76%0.099Type of chemotherapyAnthra based36.68%11.32%29.25%20.75% Taxane + Anthra based36.97%14.29%29.41%19.33%0.923Tumor size in cmsLess than 254.55%12.12%21.21%12.12% 2-546.52%13.52%27.27%12.83% &gt; 528.57%9.52%33.33%28.57%0.065OutcomeAlive without disease44.41%15.59%24.75%15.25% Alive with disease42.67%16.0%25.33%16.0% Death35.56%15.56%26.67%22.22%0.924Grade of tumorI71.43%17.86%3.57%7.14% II51.19%11.95%22.87%13.99% III23.21%16.96%39.29%20.54%&lt;0.001table 1
The triple negative subgroup was more likely to be premenopausal (p value 0.036, odds ratio 0.611, CI 0.394-0.949), have larger and grade III tumours and had worse overall survival (OS-88.46%, odds ratio 1.32, 95%CI 0.602-2.39). Patients in Her 2 enriched group also had the bad prognostic features like larger tumour size, higher grade and worst survival (OS-85.07%, odds ratio 1.78, 95% CI 0.767-4.163).However the outcome was not statistically significantly different for all the subgroups.
Conclusions:
In this tertiary cancer care hospital retrospective study of breast cancer patients in India, according to the luminal subtypes, luminal A had better prognostic features and survival compared to other subgroups.Incidence of triple negative patients was high, who were mainly premenopausal.Her 2 enriched group had the worst survival among all.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-06-10.
Abstract P4-07-04: A distinctive miRNA profile highlights breast cancer in very young women (BCVY) as a new molecular subgroup
Authors: Peña-Chilet M , Martinez MT , Perez-Fidalgo JA , Peiro-Chova L , Bermejo B , Ferrer J , Alonso E , Burgues O , Bosch A , Lluch A , Ribas G 
Published: August 2014

Abstract
Background: Although less frequent (1% of all breast cancer) than in older women, breast cancer (BC) in very young women (BCVY),(≤35 years old) often exhibits larger tumor sizes, high pathological grade, high proliferation percentage, nodal involvement, and greater HER2+ percentage, usually associated with a poorer prognosis. BC and BCVY might arise as different disease entities derived from different underlying mechanisms.
MicroRNAs (miRNAs) are short RNA molecules with post-transcriptional regulatory function, usually silencing targeted mRNAs. Recently, miRNA profiling has arisen as major approaching study technique, demonstrating a widespread miRNA deregulation in various tumor types.
In this study we offer a miRNA profile of a subset of BCVY patients and evaluate whether there are any miRNA deregulated pointing out some pathway to better understand the ongoing mechanism and characterize BCVY as a new molecular entity.
Material and methods: We performed a comprehensive study of miRNA expression using miRNA Affymetrix 2.0 array. We extracted RNA from FFPE tumor tissue of both 44 BC patients ≤35years (BCVY) and 46 older than 45years in two age groups (45-65 and &gt;65), we used normal breast tissue as control and evaluated the differences in expression of each age group. We tried to validate most interesting miRNA by qRT-PCR. We performed enrichment analysis of multiple miRNA target genes (DIANA mirpath) to search for putative pathways that could be deregulated by the miRNAs.
Results: We obtained a differential and unique miRNA expression profile of 121 miRNAs (p-value&lt;0.05), 96 of those with FDR&lt;0.05. After hierarchical clustering, samples were unsupervised grouped according to their age, neither by subtype nor by tumor characteristics. Of the 11 miRNA selected for validation, we were able to validate differences in the expression of 6 miRNAs: miR-1228*, miR-3196, miR-1275, miR-92b, miR-139, miR-1207, moreover, all of the miRNAs maintained the expression's trend. The validated miRNAs pointed out pathways related with cell motility and invasion (adherens junction, chondroitin sulfate biosynthesis, cell adhesion molecules) and cell proliferation (calcium signaling, wnt signaling).
Conclusion: We performed a comprehensive study of the miRNA expression on a total of 89 BC patients, detecting a differential molecular profile in BCVY patients, suggesting that there might be a different underlying mechanism and that BCVY could be identified as a different entity.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-07-04.
Abstract P4-07-10: MicroRNAs as biomarkers and therapeutic adjuvants for the prognosis and treatment of drug-resistant breast cancers
Authors: Chang Y-F , Pannerdoss S , Zoghi B , Jatoi I , Rao MK 
Published: August 2014

Abstract
Intrinsic and acquired resistance to antineoplastic agents continues to be a major clinical impediment to successful treatment of cancer in general, and breast cancer in particular. For example, about 40% of ER-positive metastatic breast tumors fail to respond to tamoxifen therapy, and of those that initially respond many will eventually develop resistance. Similarly, taxanes used as a first-line chemotherapy agent will have a response rate of 50%, which comes down to 20–30% in second- or third-line chemotherapy; nearly half of the treated subjects do not respond to it and suffer side effects. These facts underscore the importance of understanding the mechanism of resistance, which is crucial for the optimal systemic therapy of breast cancer. Unfortunately, in spite of extensive inquiry in this field, little is known about the key molecules/signaling pathways that regulate this phenomenon. Recently, we have discovered that small non-coding RNAs, i.e. microRNA (miRNAs), may play a critical role in mediating drug resistance in breast cancers. We have identified miRNAs that are differentially expressed between drug-resistant and sensitive breast cancer cells. Specifically, we have combined a high-throughput screening platform with a library of chemically synthesized inhibitors for all known human miRNAs and identified specific miRNA that selectively sensitize/de-sensitize drug-resistant breast cancer cells to either tamoxifen or trastuzumab (herceptin), drugs that are commonly used as a first line treatment for ER-positive and Her2-positive breast cancers, respectively. We identified 10 and 12 miRNA inhibitors that sensitized resistant cells to tamoxifen and trastuzumab, respectively. Interestingly, expression of cognate miRNA/s that sensitize resistant tumors to drug-induced cell death in our screen was found to be lower in relapsed (drug-resistant) metastatic breast cancer patients compared to normal matched control. In addition to tumor tissues, the levels of sensitizer miRNA/s in the blood sera of relapsed metastatic breast cancer patients was found to be dramatically lower than that of normal healthy individual. These findings are significant as it suggests that miRNAs can be efficiently detected in blood serum and therefore, can be used as a potential biomarker for predicting treatment outcomes. In addition, miRNAs may provide novel therapeutic tools for the treatment of drug-resistant breast cancers.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-07-10.