bluuebunny/crossref_metadata_2025_split huggingface dataset:
P3-01-15: The Role of Src Homology Phosphotyrosyl Phosphatase-2 in Basal-Type/Triple-Negative Breast Cancer – Implications for Targeted Therapy.
Authors: Agazie YM , Matalka F , Hartman ZR 
Published: June 2012

Abstract
Background: Of all breast cancer subtypes, the basal-type/triple-negative breast cancer (BTBC) has the worst clinical outcome. The major reasons are the highly invasive nature of the disease and the limited treatment options available to patients. As opposed to the HER2−positive and the hormone-positive breast cancers, targeted therapy against BTBC is unavailable. These premises underscore the need for discovering and characterizing drug targets in BTBC. In this study, we have focused on the Src homology phosphotyrosyl phosphatase 2 (SHP) which seems to play pivotal roles in BTBC. The major reason for focusing on SHP2 is that it is an essential downstream effector of mitogenic and cell survival signaling downstream of receptor tyrosine kinases such as EGFR (HER1) and IGF-1R, and the cytoplasmic tyrosine kinase Src, which are known to be elevated in BTBC.
Materials and Methods: The state of SHP2 and EGFR expression in BTBC tumors was determined by immunohistochemistry. The functional significance of SHP2 in BTBC cells was investigated by ablating its expression with specific shRNA and then assessing impact on mitogenic and cell survival signaling using immunoblotting with phospho-specific antibodies, effect on transformation using 3D cultures such as growth in soft agar and matrigel, consequence on cell motility and invasiveness using florescent-tagged matrigel. Furthermore, the impact of SHP2 inhibition on tumorigenesis was tested by intramammary transplantation in vivo and monitoring and analyzing tumor growth and metastasis.
Results: We have shown that the SHP2 protein is elevated in BTBC tumors. More importantly, the elevated expression of SHP2 is highly correlated with overexpression of the EGFR (HER1), suggesting their potential synergistic role to promote BTBC. Inhibition of SHP2 in BTBC cells reversed transformation and suppressed proliferation, indicating their dependence on the function of SHP2. Moreover, inhibition of SHP2 abolished EGF-induced mitogenic and cell survival signaling, which is in agreement with its role in cell proliferation and transformation. More dramatic was that the invasive phenotype of BTBC cells in 3D matrigel was completely blocked by inhibition of SHP2, suggesting that the invasive property of these cells is dependent on SHP2. Even more dramatic was that the tumorigenic and metastatic potential of BTBC cells was abolished by SHP2 inhibition.
Discussion: The current study demonstrates that SHP2 plays a pivotal role in promoting BTBC. Given that SHP2 is a tyrosine phosphatase with positive signaling role, its promotion of BTBC must occurs through promotion of tyrosine kinase signaling. Together, our results provide the first glimpse on the potential of SHP2 as a drug target in BTBC.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-01-15.
P3-01-16: Expression of Basal Markers in Correlation with PTEN and BRCA 1 in Triple Negative Breast Carcinomas (TN) Treated with Chemotherapy Versus PARP Inhibitors.
Authors: Chivukula M , Carter G , Puhalla S 
Published: June 2012

Abstract
The link between the BRCA1 tumour-suppressor gene and hereditary breast and ovarian cancer is established. The morphologic and immunohistochemical features of basal like phenotype carcinomas have shown to be correlated with the BRCA 1 expression. PTEN (phosphatase and Tensin Homolog) is a novel tumour suppressor gene located on chromosome 10. PTEN mutations are believed to exert their effects through the putative PI3K-AKT-mTOR signaling pathway. Lack of PTEN expression, suggests that PARP inhibitors may be therapeutically useful for a subset of invasive breast cancers. The data on PTEN status in breast carcinomas is emerging. The aim of our study is to assess the immunohistochemical expression of basal markers, PTEN and BRCA 1 in a subset of triple negative breast carcinomas with known BRCA status. Results: Results are shown in Table 1.

Conclusions: 1. Initial results from our study indicate high expression of PTEN is seen in TN breast carcinomas. 2. There appears to be decreased BRCA 1 protein expression in TN patients who tested positive for BRCA mutations. 3. Given the loss of PTEN in a subset of TN Chemo group, PARP inhibitors may be suggested to be therapeutically useful and needs to be evaluated further. 4. The lack of CK 5 basal keratin in some patients needs to be addressed further. The study is on going with addition of new cases. The updated data and preliminary data with patient responses on PARP inhibitor will be presented.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-01-16.
P3-03-08: microRNAs in Mammary Stem-Like Cells and Triple-Negative Breast Cancer; Conserved Functions and Treatment Potential.
Authors: Williams C , Aydogdu E , Katchy A , Lin C-Y , Baldosen L-A , Helguero L 
Published: June 2012

Abstract
Background: Mammary stem and progenitor cells are thought to be precursors of different subclasses of breast cancer. Triple-negative breast cancer exhibit similarities to stem or progenitor-like cells. microRNAs (miRNAs) play pivotal roles in both stem cell biology and oncogenesis. Given their potential as therapeutic targets, little is known, however, regarding miRNAs expression and functions in normal and breast cancer cells. Our objective was to identify which miRNAs are involved in mammary stem cell maintenance and differentiation and study their potential roles in triple-negative breast cancer. We investigated their expression during induced differentiation of mammary stem-like cells, correlated their expression to that of triple-negative breast cancer cells and studied the functions of the most regulated and conserved candidates.
Material and Methods: Using large-scale profiling and extensive qPCR confirmation we defined miRNAs regulated during stem-like cell differentiation. We investigated their expression in different breast cancer cell lines, and performed functional studies using miRNA mimics and inhibitors in normal stem-like cells and triple-negative breast cancer cells.
Results: Twenty-one miRNAs were strongly regulated in repeated rounds of mammary cell differentiation. The majority, including the miR-200 family and known tumor suppressor miRNAs, was upregulated during differentiation. Only 4 miRNAs, including the oncomiR, miR-17, were upregulated in the stem cell-like stage. Pathway analysis indicated complex interactions between regulated miRNA clusters and major pathways regulated during this transition, including stem cell maintenance, proliferation and differentiation. The cell model used exhibited gene expression profiles resembling basal-like poor prognosis breast cancer. Morover, we present data of miRNAs that target the genes and networks responsible for this correlation. miRNAs detected in this study can also differentiate between human non-cancer and breast cancer cell lines, and a subclass of miRNAs, was specifically downregulated in a basal-like breast cancer cell line. The functions of five miRNAs (miR-200a, -200b, -146b, -148a and -206) were further investigated. Discussion: Our findings suggest that the identified miRNAs have significant roles in biological pathways and networks associated with mammary stem/progenitor cell maintenance and triple-negative breast cancer and support their further evaluation as potential prognostic markers and therapeutic targets in the treatment of breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-03-08.
P3-05-08: Hormone Receptor Heterogeneity in Ductal Intraepithelial Neoplasia (Ductal Carcinoma In Situ) of the Breast.
Authors: Sowden M , Flynn C , Bossuyt V , Lannin D , Chagpar AB 
Published: June 2012

Abstract
Background: Ductal Intraepithelial Neoplasia [DIN] often shows heterogeneity of both morphology and nuclear grade within the same patient. It is unknown whether this implies heterogeneity with respect to hormone receptor status that may affect treatment. We sought to determine the rate of heterogeneity in terms of nuclear grade and receptor status in DIN patients.
Methods: A hospital tumor registry was queried for patients diagnosed with DIN between 1980 and 2010. Of the 746 patients identified, 579 (77.6%) had a concomitant invasive tumor. Of the remaining 167 patients, 70 were diagnosed prior to 2007 (when ASCO-CAP guidelines for hormone receptor measurements were released), 2 were found to have lobular intraepithelial neoplasia rather than DIN, and in 11 cases, pathology slides were not available for review. Of the 84 remaining patients with DIN, 17 (20.2%) had DIN 1 alone, 19 (22.6%) had DIN 2 alone, and 7 (8.3%) had DIN 3 alone. 41 (48.8%) of the patients had more than one grade of DIN. These patients formed the cohort of interest. Slides were reviewed by a single pathologist who evaluated ER and PR positivity within the different grades of DIN in each patient, classifying tumors staining 1% or greater as positive. Statistical analyses were performed using SPSS.
Results: The median patient age was 53 years old. Of the 41 patients with multiple grades of DIN, 32 (78.0%) had DIN 1 and 2, 6 (14.6%) had DIN 2 and 3, and 3 (7.3%) had DIN 1, 2, and 3 within the same tumor. 93.8%, 94.7% and 88.9% of DIN 1, 2 and 3 lesions respectively were ER-positive. A difference in hormone receptor status between different grades of DIN within the same tumor was noted in 12 (29.3%) of patients; of these 3 (10.3%) varied in ER status and 10 (34.5%) varied in PR status. Of the 2 patients with ER-negative DIN 1, both had ER-positive higher grade DIN within the same tumor. Of the 2 patients with ER-negative DIN 2, one had ER-positive DIN 1 while the other had ER-negative DIN 3. Therefore, of the total 41 patients, 40 (97.6%) had at least one component of DIN that was ER-positive, and evaluating more than one grade of DIN for ER allowed 75% of patients with at least one ER-negative component to be offered hormonal therapy.
Conclusions: Nearly 50% of patients with DIN will have more than one nuclear grade in the same tumor. These different nuclear grades vary in hormone receptor status in approximately 30% of patients. The majority of patients (97.6%) have at least one component of their DIN that is ER-positive. For those who have at least one component that is ER-negative, up to 75% may be offered hormonal therapy by considering other grades of DIN in treatment decision-making.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-05-08.
P3-06-02: Identification of Redundant, Tumor Subtype Specific Fusion Transcripts in Primary Breast Tumors.
Authors: Thompson EA , Asmann YW , Necela BM , Andorfer CA , Cunliffe HE , Hossain A , Getz JE , Hostetter G , Schroth GP , Perez EA 
Published: June 2012

Abstract
Background: The role of fusion genes and associated fusion transcripts has long been recognized in hematopoietic malignancies. Until quite recently it has been difficult to detect such events on a genomic scale in solid tumors. Consequently, little is known about the potential role of fusion genes, transcripts, and proteins as driver mutations, biomarkers, or therapeutic targets in breast cancer.
Methods: We have developed a novel analytical pipeline, Snowshoes-FTD, for detection of fusion transcripts in breast cancer cell lines and tumor samples (Asmann, et al. NAR 2011; May 27 ePub ahead of print). Preliminary analyses have been carried out with a panel of 8 each ER+, HER2+, and triple negative (TN) primary breast tumors, 8 primary human mammary epithelial cell (HMEC) lines from biopsy samples, plus 16 normal tissues from the Illumina Body Map dataset.
Results: We have identified 120 redundant, tumor-specific fusion transcripts, expressed in two or more tumors and in no non-transformed samples. Sixteen of these represent intrachromosomal fusions and 104 arise from fusion of transcripts that map to two different chromosomes. Every breast tumor expressed one or more fusion transcripts. Twenty-nine fusion transcripts appeared to be tumor subtype specific. Among these, we have identified 2 HER2+, 10 ER+, and 17 triple negative specific redundant transcripts. In general, HER2+ tumors expressed fewer fusion transcripts (range 4 to 28/tumor) compared to TN (range11 to 44/tumor). Chromosomal distribution patterns were also markedly different among the tumor subtypes. For example, ER+ tumors expressed a preponderance of redundant fusion transcripts that involve chr1 and 2, whereas TN tumors had no fusion transcripts that map to either chromosome. Conversely, the predominant locus for TN fusion transcripts was chr19, which contains only one HER2+ fusion and no ER+ fusion transcripts.
Conclusions: Primary breast tumors express many chimaeric transcripts, which we presume to arise primarily from genomic rearrangements. The majority of these transcripts are redundant, and a subset are tumor subtype specific. These transcripts may mark regions of chromosomal instability. HER2+ tumors, in general, appear to evidence less chromosomal instability, as inferred from fusion transcripts; although some HER2+ tumors appear to be quite unstable. TN tumors contain many more redundant fusion transcripts, implying increased genomic instability, particularly in chr19. We conclude that these fusion transcripts represent a class of heretofore unrecognized biomarkers that may be used for sub-classification of breast tumors. Some of these transcripts appear to encode proteins that may function as tumor-subtype-specific driver mutations and may have potential as therapeutic targets in breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-06-02.
P3-06-08: SCAN-B: An Accelerated Translational Pipeline from Profile to Prognosis and Prediction for Individual Breast Cancer Patients.
Authors: Loman N , Saal LH , Häkkinen J , Vallon-Christersson J , Ringnér M , Hegardt C , Jönsson G , Gruvberger-Saal SK , Kvist A , Reuterswärd C , Schulz R , Karlsson A , Jönsson M , Grabau D , Manjer J , Carlson J , Malina J , Larsson C , Rydén L , Borg Å 
Published: June 2012

Abstract
The South Sweden Cancerome Analysis Network - Breast (SCAN-B) Initiative is a multidisciplinary network of clinical providers of breast cancer (BC) treatment and pre-clinical scientists whose multiyear purpose is to 1) prospectively collect and analyze the “-omes” of a very large, consecutive, and population-based sample of BCs for translational research; 2) utilize this genomic data to develop new clinically-relevant biomarker assays; and 3) to build the infrastructure for future real-time clinical implementation of resultant biomarkers for individualized treatment. Patient enrollment began in the Fall of 2010 at the seven BC surgical units of the South Sweden Healthcare Region, where approximately 1500 new breast cancer diagnoses are treated yearly following the guidelines of the South Sweden Breast Cancer Group. Currently, tumor and blood samples are being collected at the rate of 80–100 patients per month, which represents approximately 75% of the catchment population. SCAN-B will initially focus on tumor transcriptome analysis using mRNA-sequencing on Illumina HiSeq 2000 instruments, and in the future multimodal data generated from other genomic platforms will also be integrated. Here we present initial experiences from this multidisciplinary collaboration including descriptions of the clinical routines, specimen handling, laboratory processing, mRNA-seq data quality control, short- and long-term projects and future directions. We believe large initiatives like SCAN-B could significantly reduce the time to discovery, validation, and clinical implementation of more powerful diagnostic, prognostic, and treatment-predictive tests for breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-06-08.
P3-07-04: Does Omission of Axillary Dissection after a Positive Sentinel Node Biopsy Influence Indication to Adjuvant Chemotherapy in Operable Breast Cancer Patients?
Authors: Montemurro F , Maggiorotto F , Valabrega G , Kubatzki F , Rossi V , Marocco F , Magistris A , Gatti M , Sarotto I , Aglietta M , Ponzone R 
Published: June 2012

Abstract
Introduction: Based on the recently published ACSOG Z0011 study (JAMA 2011;305:569), axillary dissection (AD) may be avoided in breast cancer (BC) patients with a clinically negative axilla and a positive sentinel lymph node (SLN) biopsy receiving breast conserving surgery (BCS). Because the number of positive axillary lymph nodes (ALN) is a widely accepted prognostic marker, we evaluated the potential impact of omission of AD on indication to adjuvant chemotherapy (ACT).
Patients and methods: Among 1497 patients operated at our Institution over 10 years, we identified 321 patients fulfilling the inclusion criteria of the ACSOG Z0011 study (BCS plus SLNB, cT1-2, cN0 breast cancer and 1 to 2 positive SLN). All patients underwent AD. Each case, which was anonymized, was reviewed by our breast team in two rounds. In the first round, patient age, histopathology, linfovascular invasion, tumor grade, hormone receptor, HER2, and ki67 status and number of positive SN nodes (micro and/or macrometastatic) were available. In the second round, the information on ALN was added. At each round, the panel chose between three indications: 1) Recommend ACT; 2) Discuss ACT; 3) No ACT. Results: SN was micrometastatic in 145 (45%) and macrometastatic in 176 patients (55%). ALD revealed non-SNs metastases in 96 patients (30%). Forty-four of these patients had &gt;3 positive ALN (range 4–24). Indications at round 1 and 2 are summarized below.

As a result of the disclosure of the total number of involved ALN, a change in the indication occurred in 51 patients (16%). The most frequent change was a recommendation to ACT (35 patients, 69% of the changes). Among these patients, 9 changed from No-ACT to recommend ACT. All except one change in the indication to ACT occurred in patients with immunohistochemically defined Luminal A and Luminal B/HER2 negative tumors and were mostly towards ACT. Conclusions: Omission of AD in patients with a positive SLN receiving BCS would have altered the indication to ACT in 16% of the patients at our Institution. Changes occurred almost exclusively in patients with hormone receptor positive/HER2−negative tumors. The implications of omission of AD must be taken into account before its widespread acceptance, including the possibility of a biologically tailored surgical approach.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-04.
P3-07-20: An Independent Assessment of Seven Nomograms for Predicting the Probability of Additional Axillary Nodal Metastasis after Positive Sentinel Lymph Node Biopsy in a Cohort of British Breast Cancer Population.
Authors: Nadeem RM , Gudur LD , Saidan ZA 
Published: June 2012

Abstract
Background
Axillary lymph node dissection (ALND) is currently the recommended procedure in patients with positive sentinel lymph node (SLN) biopsy. A significant proportion of patients with positive SLNs will not have any additional metastasis in non-sentinel lymph nodes (NSLNs). Nomograms could identify a subgroup of patients with low risk of further disease in whom completion ALND can be avoided. The aim of this study is to assess the accuracy of currently available seven nomograms in a cohort of British breast cancer population.
Methods: 138 patients with positive SLNs who underwent completion ALND between October 2006-April 2011 were identified. Multiple pathological variables including the histological size of the SLNs metastasis were analysed. Data was then used to calculate the probability of further metastasis in non-SLNs according to the seven nomograms that are currently in use: MSKCC, Cambridge, Turkish, Stanford, MDACC, Tenon and MOU models.
The area under the receiver-operator characteristic (ROC) curve (AUC), 95% confidence intervals, false negative and positive rate were calculated for each nomogram. Subgroup analysis includes pathological tumour size (≤ 2 cm and &gt;2 cm) and macro- or micrometastasis in SLNs. AUC value ≥ 0.80 has an excellent discriminative power.
Results: 56 of 138 patients (41%) had additional metastasis in non-SLNs.
AUC values with 95% confidence intervals and false negative rate are shown in table 1.

46/138(33.3%) had tumour size ≤ 2cm and 18/46( 39 %) had additional NSLNs metastasis. AUC values for the subgroups are shown in table 2.

19/138(14%) who had micrometastasis in SLNs, additional non-SLNs metastasis was seen in only one patient and AUC values were imprecise.
Subgroup analysis identified 6 patients with micrometastasis and tumour size ≤ 2 cm, none had additional NSLNs metastasis so AUC values cannot be computed. 19/138(14%) who had extracapsular extension, additional non-SLNs metastasis was seen in 12/19(63%).
Conclusion: MOU nomogram was more predictive than the other nomograms with a better AUC value and false negative rate. Subgroup analysis also shows persistently better AUC value for MOU nomogram. None of the models were able to achieve an AUC value ≥ 0.80 in a cohort of British breast cancer patients.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-20.
P3-07-26: How Generalizable Is the Patient Population Enrolled in ACOSOG Z11?
Authors: Lannin DR , Killelea BK , Grube BJ , Horowitz N , Chagpar AB 
Published: June 2012

Abstract
Background: The recently published Z11 trial of observation vs. axillary dissection for patients with a positive sentinel lymph node showed amazingly low axillary recurrence rates in both groups, and has the potential to dramatically alter practice. However questions remain about whether the Z11 population is representative of the larger population of breast cancer patients.
Methods: An institutional database was queried to identify all patients who underwent sentinel node biopsy at our breast center from 2004 to 2010. These cases were retrospectively reviewed to determine the percentage of patients who would have met the Z11 eligibility requirements, and the demographics and outcomes for this subset were compared to those for Z11.
Results: Out of 1215 patients undergoing sentinel node biopsy, 282 (23%) had at least one positive sentinel node. However when patients were eliminated who had T3 or T4 tumors, more than 2 positive sentinel nodes, neo-adjuvant chemotherapy, or who underwent mastectomy, only 88 remained who would have been eligible for Z11 (31% of those with a positive sentinel node). These patients are compared to the Z11 patients in the following table.

Our lumpectomy patients were generally quite similar to those of Z11 except ours had a lower percentage of micrometastases and a higher percentage of 4 or more positive nodes. As with most other published prediction models, the chance of having 4 or more positive nodes in our patients was directly proportional to tumor size and number of positive sentinel nodes, and inversely proportional to number of negative sentinel nodes.
Conclusions: A relatively small percentage of node positive patients at our institution actually met the eligibility requirements for Z11, but this subset was similar in most respects to the Z11 population. We have developed an algorithm that can be prospectively tested that will allow the majority of these patients to forego axillary dissection but that will exclude patients most likely to have 4 or more positive nodes.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-26.