bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-06-09: Test of association between Ki67 index of early breast cancer and local relapse after adjuvant hypofractionated radiotherapy.
Authors: Rodrigues DN , Somaiah N , Daley F , Davies S , Rakha E , A'Hern R , Haviland J , Sydenham M , Owen R , Reis-Filho J , Yarnold JR 
Published: August 2014

Abstract
Introduction: There is a strong inverse association between the proliferation indices of early- and late-responding normal tissues and their sensitivity to radiotherapy fraction size. The aim of this study is to test for association between Ki67 index and the fractionation sensitivity of breast cancer. The hypothesis is that tumours with high Ki67 indices are relatively insensitive to fraction size and be over-represented in tumours relapsing after hypofractionated, radiotherapy.
Methods: Between 1986 and 2003, the START pilot and START A trials tested 2 test dose levels of a 13-fraction regimen (3.0 or 3.3 Gy & 3.0 or 3.2 Gy fractions, respectively) in 5 weeks against 25 fractions of 2.0 Gy following primary surgery for early breast cancer. Primary tumour blocks of patients with local tumour relapse were collected for immunohistochemistry (IHC) for Ki67 (manual counting in whole sections), HER2, ER & PR (Allred quick scores in tissue sections). Ki67 was assumed to be log normally distributed with a standard deviation of 0.5–0.9. Assuming evaluable blocks for 240 patients, a standardised detectable difference of 0.45 (90%+ power, 5% significance level) corresponded to a detectable difference in geometric means of 5–10%.
Results: From a total of 3646 patients entered into the START pilot and START A trials, 261 local tumour relapses were recorded at a median follow up of 8.4 years (range 0.9–17.5) and 7.2 (range 0.7–11.9) years respectively. Blocks from 213 patients were recovered, of which 176 were evaluable by IHC. There was no significant difference in proliferation between tumours relapsing after conventional and hypofractionated radiotherapy, with mean Ki67 scores of 7.63 (95%CI: 5.06–11.5) and 5.33 (95CI%: 3.86–7.35), respectively. Mean Ki67 scores in 48 primary triple negative tumours (TNT) that relapsed locally were 15.74 (95%CI: 8.53–29.06) after conventional and 7.52 (95%CI: 3.51–16.1) after hypofractionated radiotherapy, but TNT were equally represented (28%) in both groups.
Conclusion: An association between proliferative indices and fractionation sensitivity in breast tumours has not been demonstrated. If confirmed, it suggests that genetic and epigenetic features unrelated to proliferation are sources of inter-tumour variation in fractionation sensitivity.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-09.
Abstract P3-06-32: Topoisomerase 1 gene copy aberration is a frequent finding in clinical breast cancer samples
Authors: Stenvang J , Smid M , Nielsen S , Balslev E , Timmermans M , Rømer M , Nygaard S , Christensen I , Nielsen D , Foekens J , Brünner N , Martens J 
Published: August 2014

Abstract
Background: The topoisomerase-1 (TOP1) targeting drug irinotecan may be a new effective drug in the treatment of metastatic breast cancer patients1,2. However, the use of irinotecan should be guided by predictive biomarkers to avoid drug-induced site effects in the non-responding subgroup of patients. A newly developed TOP1 fluorescence in situ hybridization (FISH)3 probe mix (Dako, Denmark) may represent such a novel predictive biomarker assay.
Materials and Methods: The TOP1/CEN-20 FISH probe mix was applied to normal breast tissue (n = 100) and human breast cancer biopsy material (n = 42). TOP1 copy number variations (Affymetrix GeneChip 100k SNP array) and TOP1 mRNA levels (Affymetrix u133a GeneChip) were studied in 313 breast cancer samples4.
Results: Employing FISH, the mean diploid TOP1 copy number in normal breast epithelium was 1.7 (range 1.45–1.90) and the diploid CEN-20 number was 1.6 (range 1.38–1.82). The normal diploid range was defined as the mean plus/minus 0.5 times the haploid gene copy number (Table 1 and 2). Using these values as cut-off, 13 (30.9%) of the 42 breast cancer samples had TOP1 gene copy number in the diploid range, 18 (42.9%) had 1 extra copy and 11 (26.2%) had ≥ 2 extra copies. CEN-20 counts showed that 19 (45.5%) had CEN-20 values within the diploid range, 21 (50%) had 1 extra copy and 2 (4.8%) had ≥ 2 extra copies. Calculating the TOP1/CEN-20 ratio showed that 6 (14.3%) of the patients samples had a ratio above 1.5, while none had a ratio &lt; 0.8. The Pearson correlation between TOP1 and CEN-20 counts in the 42 breast cancer samples analyzed with FISH was 0.73. In the 313 breast cancer samples 34/313 (10.9%) had TOP1 copy gain and a significant association (p &lt; 0.0001) was observed between TOP1 copy number and TOP1 mRNA.
Conclusions: This study shows that about 25% of breast cancers have ≥2 extra copies of TOP1 as determined by FISH analyses. The high correlation between TOP1 and CEN20 in the 42 breast cancer samples challenges the use of the ratio. Moreover, the significant association between TOP1 gene copy number (SNP array) and TOP1 mRNA expression in breast cancer biopsies suggests that TOP1 FISH results will correlate with TOP1 protein amounts and may therefore be used to predict sensitivity to the TOP1 targeting drug irinotecan in breast cancer. However, a prospective clinical study is needed to prove or disprove this hypothesis.

References
1. Perez EA et al. J Clin Oncol. 2004, 22(14):2849–55. 2. Lee KS et al. Invest New Drugs. 2012 May 5. 3. Rømer MU et al. Scand J Gastroenterol. 2012, 47(1):68–79. 4. Zhang Y et al. Cancer Res 2009, 69(9):3795–3801.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-32.
Abstract P4-14-14: Phyllodes tumour of the breast: A retrospective analysis of 87 cases
Authors: Walter HS , Esmail F , Krupa J , Ahmed SI 
Published: August 2014

Abstract
Background: Phyllodes tumour is a rare fibroepithelial tumour of the breast that accounts for only 0.5% of all breast neoplasms.
Methods: We retrospectively reviewed the case notes of all patients with phyllodes tumour treated between 1987–2010. Clinical data was analysed with respect to pathological and treatment outcome data.
Results: Between 1987–2010, 87 patients were treated for tumours, histologically classified as benign (60), borderline (10) and malignant (17). Median age at presentation was 55 years for patients with malignant phyllodes, 45 years for benign phyllodes and 48 years for patients with borderline tumours. Primary surgery for patients with benign or borderline phyllodes in 68 cases was breast conserving with 2 patients undergoing mastectomy. Of those with malignant phyllodes, primary surgery for 6 patients was mastectomy and 11 patients had breast conserving surgery. 2 patients with malignant phyllodes received adjuvant radiotherapy, to the chest wall for recurrence following mastectomy in one patient and following local excision in the other patient. 2 patients with malignant phyllodes proceeded to axillary surgery, with no involvement of lymph nodes. 6 patients (8.6 %) with benign disease and 4 (23.5 %) with malignant phyllodes had a local recurrence. Of those with malignant phyllodes who had a recurrence, 2 had systemic metastases and all had had a local excision at presentation. Median time to development of metastatic disease from initial presentation was 2.5 years. 1 patient received 1 cycle of palliative doxorubicin but progressed through treatment. Relapse free survival to date for patients with benign, borderline and malignant phyllodes was 91.7 %, 90 % and 70.6 % respectively.
Conclusion: Phyllodes tumours form a heterogenous group with a spectrum of behaviour in terms of risk of local recurrence and metastases. From this series, malignant phyllodes have a higher recurrence rate than benign and borderline tumours. Local excision in this group was associated with a 36.4 % local failure rate and 18.2 % risk of systemic metastasis. Treatment for malignant phyllodes should be individually based, but the greater risk of relapse both locally and systemically, should be taken into consideration and the options of mastectomy or oncoplastic techniques considered.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-14-14.
Abstract AL-1: AACR outstanding investigator award for breast cancer research: Understanding estrogen receptor transcription in breast cancer
Authors: Carroll JS 
Published: August 2014

Abstract
Estrogen Receptor (ER) is the defining feature of luminal breast cancers, where is functions as a transcription factor. The traditional view of ER getting recruited to promoters of target genes is too simplistic. The recent discovery of ER-DNA interaction regions from ER+ breast cancer cell lines has revealed that ER rarely associates with promoter regions of target genes and instead associates with enhancer elements significant distances from the target genes. The genomic mapping of ER binding events also revealed the enrichment of DNA motifs for Forkhead factors. The Forkhead protein FoxA1 (HNF3a) was subsequently shown to bind to half of the ER binding events in the genome and was required for ER to maintain interaction with DNA. We have extended on these findings to explore ER and FoxA1 functional interactions in breast cancer, with a specific focus on changes in binding dynamics that occur during endocrine resistance. To this end, we have established transcription factor mapping approaches (ChIP-seq) in primary tumor material, to investigate differential ER/FoxA1 binding that occurs during tumor progression. We have functionally explored underlying factors that contribute to altered transcription factor binding and activity. In addition, we have recently established a method for rapid unbiased discovery of protein interacting complexes, which we have applied to discover ER associated proteins. We find an unexpected interaction between ER and progesterone receptor (PR) in ER+ breast cancer. We show that PR is a negative regulator of the ER complex, where it is important for modulating ER-DNA interactions and cellular growth. These findings help delineate the complexes that influence ER transcriptional activity and ultimately impinge on tumor progression and drug sensitivity.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr AL-1.
Abstract BS02-1: Hypoxia metabolism in breast cancer – How to overcome resistance to anti-angiogenic therapy
Authors: Harris AL , Buffa FM , Haider S , Bensaad K , McIntyre A , Lord S , Mehta S , Choudhry H , Favaro E , Ledaki I , Singleton D 
Published: August 2014

Abstract
Background. Hypoxia is recognised to induce a multigene programme mainly via HIF1a and also HIF2a transcription factors. Bioinformatics analysis of multiple gene array data sets in breast cancer showed a core hypoxia response programme of approximately 90 genes associated with poor outcome independently of other factors. This core response was significantly over-expressed in triple receptor negative cancers. Additionally, microRNAs associated with hypoxia were shown to give additional worse prognosis associations (mir-210). mir-210 targeted the mitochondrial iron chaperone responsible for regulation of key enzymes in the Krebs cycle and showed an adaptive response to hypoxia involving switching off the mitochondrial metabolism.
Aims and methods. To assess in human breast cancer the hypoxia transcriptome we conducted gene microarray studies before and after 2 weeks of bevacizumab 15mg/kg single dose before neoadjuvant chemotherapy. This was correlated with imaging by DCE-MRI Ktrans analysis.
Results. The study showed that high Ktrans was an excellent predictor for the biological affect of VEGF inhibition and extensive gene induction occurred, including many components of the HIF pathway, but also glycogen metabolism and lipid metabolism.
We investigated these further in xenograft models to see which of the adaption pathways may be most important for survival under hypoxic conditions. We showed that induction of CA9, a key enzyme regulating extracellular pH, was critical for survival under anti-angiogenic therapy and blocking CA9 could synergise and also produce radiosensitivity. Reactivating mitochondria under hypoxic conditions induced by angiogenesis also showed additional anti-cancer benefits and is the basis now for a new phase I study in our department.
Additionally, surprisingly, induction of glycogen and lipid storage occurred and this was essential for survival on reoxygenation and for protection against free radical damage, which greatly increased when either pathway was inhibited.
We investigated, by bioinformatic approaches, the expression of 133 key enzymes in metabolism, showed that they were strongly associated with different subtypes of breast cancer, which may help in selection of patients for future intervention studies.
To additionally define the hypoxia transcription, we conducted RNA sequencing of MCF7 cells in normoxia and mild hypoxia. This revealed marked induction of many long non-coding RNAs, suppression of all transfer RNAs and induction of novel antisense RNAs.
Conclusions. Overall, therefore, although anti-angiogenic therapy alone is now withdrawn from clinical utility in breast cancer, the massive induction of hypoxic microenvironment and synergy with many other therapeutics, suggests that as new approach using induced essentiality should be reassessed in breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr BS02-1.
Abstract BS02-2: Alterations in tumor metabolism to support breast tumor growth and progression
Authors: Vander Heiden M 
Published: August 2014

Abstract
Breast cancer cells must adapt metabolism to support anabolic processes and allow the accumulation of biomass to allow proliferation. However, tumor cells also experience periods of stress, and metabolic plasticity to shift metabolism to maximize efficiency and survive nutrient limitation is also needed for cancer progression. The M2 pyruvate kinase isoform (PKM2) is expressed in cancers and plays a role in regulating metabolism. To determine whether PKM2 is required for the development and growth of primary breast tumors, we generated mice harboring a conditional allele for PKM2. PKM2 deletion selectively abolishes PKM2 protein production while continued production of PKM1, the other major pyruvate kinase isoform. We crossed PKM2 conditional mice to a model of human breast cancer driven by loss of the Brca1 tumor suppressor gene. Contrary to prior expectation, mammary tumor formation and progression was accelerated despite PKM2 deletion. PKM2-null tumors displayed heterogeneous compensatory PKM1 expression, and expression of PKM1 was observed only in non-proliferating tumor cells. In contrast, proliferating cells in the tumor had no detectable pyruvate kinase expression. This suggests that PKM2 protein is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, while cells with active pyruvate kinase are involved in aspects of tumor progression that do not involve proliferation. Consistent with these findings, variable expression of PKM2 was observed across a panel of human breast tumors, and recurrent mutations resulting in disruption of one PKM2 allele are found in multiple human cancers. Together, these data support a model where regulation of PKM2 activity allows the enzyme to support the differential metabolic requirements of both proliferating and non-proliferating tumor cells.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr BS02-2.
Abstract ES04-2: Understanding nuclear receptor in breast cancer
Authors: Fuqua SAW 
Published: August 2014

Abstract
Breast cancer cells have receptors on the surface, in the cytoplasm and in the nucleus. Chemical messengers such as steroid hormones bind to receptors, and this causes changes in the transcriptional program of the cells. Breast cancer cells may express two important steroid receptors: estrogen receptor s alpha and beta (ERs a and b, respectively), and/or progesterone receptor (PR). ER-positive cancer cells depend on estrogen for their growth, so they can be treated with drugs to block estrogen effects (e.g. tamoxifen), or which block estrogen synthesis (Cyp19 [aromatase] inhibitors or Cyp19 inhibitors which block both androgen and estrogen synthesis. Cells which express more of these receptors generally respond better to hormonal therapies.
The ERs are from a large family of nuclear receptor transcription factors (TFs). When bound by hormone (they bind to DNA directly or they can interact with other transcription factors bound to DNA to regulate gene expression. ER and PR acts by recruiting a complex of coactivator or corepressor proteins that modulate ER functions. These coactivators are important regulatory molecules, and evidence suggests that some are oncogenes, capable of causing breast cancer and showing gene amplification and/or over-expression in a ER-psositiv breast cancers, thus affecting tumor growth and treatment.
Many mechanisms for resistance to endocrine therapies have been postulated and the loss of ER over time although not common can happen. The evolution of receptor mutations over time perhaps in tumor subpopulations has also been postulated, and recent evidence suggests that they occur more frequently than once thought in ER-positive metastatic gtumors. In addition, the PR is frequently lost or altered, which can result from its activation from upstream growth factor receptors. Coactivators that are overexpressed can also modulate ER function so that tumors fail to respond to blocking ER therapies. The basic biology, function, and altered mechanism of action of ER/PR which occur during tumor evolution will be discussed in this educational session.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES04-2.
Abstract ES05-1: Global trends in breast cancer incidence and mortality
Authors: Porter PL 
Published: August 2014

Abstract
Although breast cancer remains a disease most prominent in affluent countries, there is clear evidence that the risk of breast cancer, and most troubling, the risk of death from breast cancer is now a global concern. Data from global databases show incidence rates of breast cancer increasing in virtually all geographical regions since 1973. There are over 1 million new cases of breast cancer worldwide each year, and forty five percent of those cases occur in the less developed countries. Virtually all emerging countries are faced with the challenge of detecting, registering and treating a disease that in the past was considered too infrequent or too low on the list of deadly threats to waste precious health dollars.
The presentation will address global and regional trends in breast cancer incidence and mortality as well as reasons for disparities in mortality and strategies to alter current trends.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES05-1.
Abstract OT1-1-01: Optimizing neoadjuvant systemic treatment in HER2 positive breast cancer - The TRAIN-2 study
Authors: van Ramshorst MS , van Thienen JV , Stouthard JM , Rodenhuis S , Linn SC , Sonke GS 
Published: August 2014

Abstract
Background Anthracycline-based regimens are still commonly used in HER2 positive (HER2+) breast cancer (BC), despite added toxicity compared to non-anthracycline containing regimens. The benefit of antracyclines in the era of trastuzumab containing regimens is controversial. Moreover, the value of anthracyclines in combination with dual-HER2 blockade is uncertain. We recently showed high pathologic complete response (pCR) rates with a weekly neoadjuvant paclitaxel-trastuzumab-carboplatin (PTC) regimen. We now aim to evaluate the effect of replacing 3 PTC cycles in this regimen with 3 FE90C-trastuzumab cycles, while adding pertuzumab to all cycles in both arms.
Secondly, combined blockade of the estrogen-receptor (ER) pathway and the HER2-pathway in the presence of chemotherapy has not previously been investigated in HER2+/ER+ tumors.
Trial design This is a randomized comparative trial evaluating pCR rate (ypT0/is ypN0) at surgery as primary endpoint after neoadjuvant systemic therapy with 9 cycles PTC plus pertuzumab q3w (paclitaxel 80mg/m2 day 1, 8 – trastuzumab 6mg/kg (loading dose 8mg/kg) day 1 – carboplatin AUC = 6 day 1 – pertuzumab 420mg (loading dose 840mg) day 1) versus 3 cycles FE90C-T plus pertuzumab q3w followed by 6 cycles PTC plus pertuzumab q3w.
An optional second randomization (2×2 factorial design) will compare concurrent endocrine treatment with an aromatase inhibitor (and ovarian function suppression in premenopausal women and men) during neoadjuvant chemotherapy in combination with dual HER2-blockade, in patients with HER2+/ER+ tumors.
Eligibility criteria Patients aged ≥18 year with histologically confirmed invasive HER2+ BC, stage II or III. Eligible patients have a performance status of 0 to 1 and adequate cardiac and organ function.
Specific aims The primary objective is to compare the efficacy of 6 cycles neoadjuvant PTC plus pertuzumab preceded by either 3 cycles FE90C-T plus pertuzumab or 3 cycles PTC plus pertuzumab in stage II and III HER2+ BC.
Secondary objectives are to describe the efficacy of combined HER2 and ER pathway blockade in HER2+/ER+ BC, to describe the safety of the various regimens and to identify prognostic and predictive biomarkers for pCR.
Statistical methods The sample size of the study will be based on the primary objective. To detect an increase in pCR rate from 44% in the PTC arm to 58% in the FE90C-T arm at the 5% (2-sided) level of significance with an 80% power 437 patients need to be randomized (assuming ∼10% of patients will be not evaluable).
Target accrual Recruitment will start in the summer of 2013 across ∼30 sites in the Netherlands. Unrestricted research support and pertuzumab are kindly provided by Roche Netherlands. The trial is sponsored by the Dutch Breast Cancer Trialists’ Group (BOOG).
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-01.