bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract BSF1-2: Understanding Stem Cells To Get Abreast of Breast Cancer
Authors: Lindeman GJ 
Published: April 2011

Abstract
Gene profiling studies have provided a basis for classifying breast cancer into at least six molecular subtypes and stimulated interest in identifying the cell type in which these distinct subtypes arise. Elucidating the normal cellular hierarchy within breast tissue is essential for identifying the ‘cell of origin’ that is targeted for neoplastic transformation. Stem cells, which lie at the apex of the normal tissue hierarchy, represent strong candidates, given that they are long-lived and capable of self-renewal. Alternatively, committed progenitor cells (stem cell descendants) or even mature progeny could also serve as cells of origin in breast cancer. Under these circumstances, cells would need to acquire certain stem cell-like properties (such as self-renewal) during tumorigenesis.
Our group (and others) have isolated discrete subpopulations of mouse and human mammary epithelial cells on the basis of cell-surface markers and defined subsets that are highly enriched for basal/mammary stem cells, committed luminal progenitor cells and mature luminal cells. Gene profiling revealed remarkable similarities between their molecular signatures and certain subtypes of breast cancer. Notably, the luminal progenitor signature (and not the basal/stem cell signature) was most similar to basal-like breast cancer. Moreover, breast tissue from breast cancer prone BRCA1 mutation carriers was found to contain increased numbers of luminal progenitors, which had aberrant growth and differentiation properties. Taken together, these findings suggest that luminal progenitors (and not basal/stem cells) are the likely target that give rise to basal-like breast cancer. Key markers (such as KIT) expressed by luminal progenitor cells could serve as therapeutic targets for breast cancer prevention or therapy. The cancer stem cell (CSC) hypothesis is in many ways distinct from the ‘cell of origin’ concept. This model proposes that established tumors are hierarchically organised (like normal tissue) and contain a subpopulation of cells with tumor propagating ability. CSCs are not necessarily derived from transformed stem cells. However, CSCs do need to acquire key stem cell properties (such as self-renewal capability). Breast CSCs have now been identified by several groups using xenograft models. Our laboratory has studied syngeneic mouse models of mammary tumorigenesis and found that a subset (but not all) appear to conform to the CSC hypothesis. The luminal progenitor marker (CD61/≥3-integrin) was found to identify a CSC population in mammary tumor-prone MMTV-wnt-1 and BALB/c-p53+/−, but not in MMTV-neu/erbB2 mice. We speculate that the CSC model may not necessarily apply to all breast tumors. Rather, the conventional ‘clonal evolution’ model (or perhaps a hybrid model) may also be relevant in some cases of breast cancer.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr BSF1-2.
Abstract BSF2-1: Molecular Chaperones: Cancer Dependence and Druggability
Authors: Workman P 
Published: April 2011

Abstract
Cancer cells live in a stressed state caused by genomic abnormalities, deregulated biochemical pathways and microenvironmental pressures. As a result they evolve, during malignant transformation and progression, a dependency on a range of molecular chaperone systems that provide essential protein folding, oncoprotein activation and anti-apoptotic functions. This chaperone dependence creates a specific vulnerability in cancer cells that is now being actively exploited in drug discovery. Our own work has focused on using a combination of genetic techniques and chemical probes (a powerful combination, see Workman P, Collins I. Probing the probes: fitness factors for small molecule tools. Chem Biol 17 561-577 2010) to enhance our understanding of the cancer biology of molecular chaperone systems. At the same time we are heavily involved in the discovery and clinical evaluation of drugs that act on these cancer-supportive molecular machines. The trail has been blazed by HSP90 inhibitors, of which at least 13 are now in clinical development. Signs of clinical activity have been seen, most notably with 17-AAG (tanespimycin) in trastuzumab-refractory, ERRB2-positive breast cancer. The new HSP90 inhibitor NVP-AUY922, which we discovered with Vernalis and is being developed by Novartis, shows good activity in breast tumour models (Eccles SA et al NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumour growth, angiogenesis, and metastasis. Cancer Res 68 2850-2860 2008). The activity of HSP90 inhibitors is self-limited by the mechanism-based activation of the protective, HSF1-dependent heat shock response. This presentation will provide an update on the discovery, development and use of HSP90 inhibitors and will describe emerging data on the identification and validation of new potential chaperone system targets, including AHA1, CDC37 and the HSP70 family (eg Powers MV, Clarke PA, Workman P. Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumour-specific apoptosis. Cancer Cell 14 250-262 2008). Molecular chaperones are overexpressed in clinical breast cancers, and in many examples their expression correlates with clinical outcome. Moreover, many oncoproteins important in breast cancer are client proteins for HSP90, including ER, PR, ERBB2, AKT/PKB/and CRAF. Thus HSP90 and other chaperone inhibitors have particular potential in breast cancer. Progress towards, and future challenges for, the potential of anti-chaperone drugs to become part of the personalized cancer medicine of the future (Yap TA, Sandhu SK, Workman P, de Bono JS. Envisioning the future of early anticancer drug development. Nat Rev Cancer 10 514-523 2010) will be highlighted.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr BSF2-1.
Abstract CSF1-2: Controversies in Screening for Breast Cancer
Authors: Esserman LJ 
Published: April 2011

Abstract
Over the last 10 years, we have learned a great deal about breast cancer. We now know that all breast cancers are not the same. Whether defined by receptor status or molecular subtype, we now know that there is a range of growth rates and associated risk of metastases for each breast cancer subtype. It stands to reason then that the impact of screening is likely to be different for each breast cancer subtype. And of course, every woman is not the same, and consideration of both genetic predisposition and the context of competing health risks should play a role in optimizing screening strategies for women. The goal of this talk is to integrate these considerations with the observations on breast cancer incidence over the past 25 years since the advent of screening. The rise in the incidence of early stage disease, particularly for women over the age of 50, has not been accompanied by a commensurate decline in the incidence of regional cancers. Regional or more locally advanced cancers are more likely to present at younger ages, and as interval cancers. On the other hand, indolent disease is more likely to appear in women of older age. This knowledge helps us to understand how to better personalize screening recommendations and better understand the screening trial data and the differential impact by age as well as the US Preventive Services Task Force screening guidelines. The screening trials also reflect an era when systemic treatment was quite different than it is today. Moreover, recent data suggest that the impact of optimal systemic treatment reduces the impact of screening. Finally, we must take into account the fact that screening is more likely to detect indolent cancers (IDLE tumors) when they are present. These insights present opportunities to improve our approach to screening which may in turn reduce the burden of cancer and cancer diagnosis.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr CSF1-2.
Abstract ES9-3: Balancing Risks of Deconditioning vs. Weight-Lifting for Breast Cancer Survivors
Authors: Schmitz KH , Cheville A , Ahmed RL , Troxel A 
Published: April 2011

Abstract
Background: Clinical guidelines for breast cancer survivors with and at-risk for lymphedema have advised against upper body exercise, preventing them from obtaining established health benefits of weight-lifting. The primary hypotheses of the Physical Activity and Lymphedema Trial were that lymphedema onset and worsening would not differ after a one-year weightlifting intervention compared to no exercise among survivors at risk for and with breast cancer-related lymphedema.
Methods: We performed a randomized controlled trial of a twice-weekly progressive weight-lifting intervention involving 141 breast cancer survivors with stable arm lymphedema at study entry and 154 survivors at-risk for lymphedema at study entry. Treatment group participants were provided a gym membership and 13 weeks of supervised instruction; the remaining nine months were unsupervised. Control group participants were provided the intervention after study completion. The primary outcome was the change in arm swelling at one year, as measured by water volumetry of the affected and unaffected arms. Secondary outcomes included the clinician defined incidence of onset and exacerbations of lymphedema, lymphedema symptoms, and muscle strength. Participants with lymphedema were required to wear a well-fitted compression garment while weight-lifting.
Results: Among the women who entered the study with lymphedema, the proportion who experienced a 5% or greater increase in arm swelling (interlimb difference) was similar in the treatment and control groups (11% versus 12%; cumulative incidence ratio [95% confidence interval], 1.00 (0.88 to 1.13) As compared with the control group, the women in the intervention group with lymphedema had greater improvements in self-reported lymphedema symptom severity (p=0.03), and a lower incidence of lymphedema exacerbations as assessed by a certified lymphedema specialist (14% versus 29% in the control group, p= 0.04). Among the women who entered the study without lymphedema, more control than treatment group women experienced lymphedema onset defined by 5% increase in interlimb difference (17 versus 11%, p = 0.35). Among higher risk women (5+ lymph nodes removed), this comparison was statistically significant (22 versus 7%, p=0.04). Clinician-defined BCRL onset occurred in 1 treatment and 3 control group women (p=0.62).
Conclusions: Slowly progressive weight-lifting had no significant impact on arm swelling among breast cancer survivors with lymphedema, and resulted in a reduced incidence of lymphedema flares and improvement in symptoms. In breast cancer survivors at risk for lymphedema, a program of slowly progressive weight-lifting, compared with no intervention, did not result in increased incidence of lymphedema. In secondary analyses, women with 5+ nodes removed who did weight-lifting were less likely to experience increases in arm swelling.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr ES9-3.
Abstract P1-01-01: Learning Sentinel Node Biopsy in the UK: Results of the NEW START Training Program
Authors: Mansel R , Goyal A , MacNeill F , Newcombe R , Layer G , Kissin M , Horgan K , Britten A , Hilson A , Clarke D , Townson J , Ell P , Wishart G , Brown D , West N , Keshtgar M. 
Published: April 2011

Abstract
Background: NEW START-a structured, validated multi-professional surgical training programme, was established to allow rapid transfer of appropriate knowledge and technical skills to ensure safe and competent practice of sentinel lymph node biopsy (SLNB) across the UK.
Methods: Multi-professional teams attended a theory/skills-lab course delivering a standardized educational package, following which they performed SLNB in 30 consecutive patients, either concurrently with their standard axillary staging procedure — mentorship training model-or as stand-alone SLNB — apprenticeship training model. An accredited NEW START trainer mentored the first 5 procedures in the participants’ hospital, or all 30 if stand-alone. Validation standards were a localization rate of ≥90% and in the mentorship program where a minimum of 10 cases were node positive, a false-negative rate of ≥10%. SLNB was performed according to a standardised protocol using the combined technique of isotope (0.05-0.1ml of 99mTc-albumin colloid — Nanocoll®) and blue dye (Patent blue V) injected into the tumour quadrant peri-areolar tissue. Isotope was injected intra-dermally and static scintigraphic images were obtained, blue dye was injected sub-dermally after anaesthetic induction.
Results: From October 2004 to December 2008, 210 SLNB naive surgeons, in 103 centres, performed 6,685 SLNB procedures of which 31% (2,098/6,685) were node positive. The mentorship training model was followed in 87% (5,849/6,685). Scintigraphy identified axillary lymph node drainage in 85% (5,564/6,511) with an overall SLN localization rate of 98.9% (6,610/6,685, 95% CI 98.6% to 99.1%). Node positivity was higher (P&lt;0.001) for failed (58.7%, 44/75) than successful (31.1%, 2054/6610) localizations. The mentorship false negative rate (FNR) was 8.9% (163/1821, 95% CI 7.7% to 10.4%). The median SLN yield was 2.0 (range 1-11).
SLN localization and FNR improved with surgeon caseload so that after 20 procedures the FNR fell below 10% but no statistically significant learning curve was identified. The FNR patients who had one SLN harvested was 14.8%. The FNR rate declined to 9.4%, 6.3%, 4.5% and 4.0% for those patients with 2, 3, 4 and more than 4 SLNs removed.
Conclusion: NEW START demonstrates that a standardized injection protocol and structured multi-professional training can abolish learning curves so ensuring patient safety during national adoption of a new technique. Tumor quadrant injection using both isotope and dye has a high localization rate and low false-negative rate. Failed localization indicates higher probability of axillary nodal involvement. It is not necessary to remove more than 4 SLNs to achieve a FNR of less than 5%.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-01.
Abstract P1-01-05: Clinical Significance of Tumor Burden in the Sentinel Nodes after Neoadjuvant Therapy Differs from Sentinel Nodes in the Adjuvant Setting and This May Influence the Management of the Axilla
Authors: Rubio IT , Cebrecos I , Peg V , DiCosimo S , Cortes J , Xercavins J. 
Published: April 2011

Abstract
Background. Lymph node metastases are the most significant prognostic factor for breast cancer patients. The use of sentinel node biopsy (SLN) has generated an increased detection of positive nodes through the identification of isolated tumor cells (ITC) and micrometastasis. The objective of this study is to evaluate the significance of SLN micrometastasis and ITC for patients undergoing neoadjuvant chemotherapy versus patients undergoing surgery first.
Material and Methods. A total of 571 patients with clinically node negative T1-T3 breast cancer underwent SLN surgery from 2004 to 2008.
Clinicopathological data were reviewed and comparison was made between results in the adjuvant and neoadjuvant setting.
Results. Of the 571 patients, 71 patients (12.5%) underwent SLN biopsy after neoadjuvant chemotherapy and 500 (87.5%) underwent surgery first. The SLN identification rate in the adjuvant and neoadjuvant therapy groups were similar (96.2% vs 95.8%). Mean number of sentinel nodes removed were 2,2 (range 1-15) in the adjuvant group and 2.2 (range 1-7) in the neoadjuvant group. The SLN was positive in the adjuvant group in 151 patients (30%) while in 27 patients (37.5%) in the neoadjuvant group. The SLN was the only positive node in 106 patients (70.1%) in the adjuvant group and in 6(26%) in the neoadjuvant group. Micrometastasis in the SLN was found in 39 patients (7.8%) in the adjuvant group and in 7 (9.8%) patients in the neoadjuvant group. In the adjuvant group, 7 patients (17.9%) had additional non SLN positive in the axillary dissection (ALND), while 3 (49%) in the neoadjuvant group. ALND was performed in all patients with ITC in the SLN in the neoadjuvant setting and 50% of them had additional nonSLN.
Discussion. The significance of micrometastasis or ITC in the sentinel node seems to differ in patients with neoadjuvant therapy or surgery first. Micrometastsis or ITC in patients with prior neoadjuvant therapy may reflect residual disease in the axilla, as 50% of patients will have additional positive nodes. Completion axillary node dissection should be considered in this group of patients. Even more, the majority of patients with a positive SLN in the neoadjuvant group harbored additional positive axillary nodes.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-05.
Abstract P1-01-08: Lymph Node Ratio as an Alternative to pN Staging in Node Positive Breast Cancer: A report from the Korean Breast Cancer Society
Authors: Kim HJ , Gong KY , Jung KH , Kim S-B , Lee JW , Ahn SH. 
Published: April 2011

Abstract
Background: To compare the lymph node ratio(LNR) and pN staging as a prognostic predictor and find out high risk subgroup which can not predict prognosis using pN staging.
Patients and Methods: Using information from two large databases, including Korean nationwide registry, we compared the survival using LNR and pN stage parameters by Cox regression analysis. Moreover survival data were analysed according to age subgroups and intrinsic subtypes. Results: In an analysis of 2264 node positive patients from single institution, adjusted cancer specific mortality risks of low (≥0.20), intermediate (&gt;0.20 and ≥0.65) and high risk (&gt;0.65) LNR groups were 1(reference), 1.9 (95%CI, 1.6 to 2.4), 4.6(95%CI, 3.6 to 5.8). The difference of mortality risk between LNR parameters were wider than that of N1, N2 and N3 in DFS, CSS, OS. In contrast to LNR risk categories, survival curve in pN1 and pN2 overlapped in the patients below 35 years old. Survival curve in pN1 and pN2 also overlapped in patients in her2/neu enriched as well as triple negative subtype. These finding were validated by an analysis of nationwide registry data on 15488 node positive patients. The patients who had N1 and LNR2-3 disease showed poor DFS (HR 1.7 95% CI 1.4 to 2.2) and CSS (HR 1.6, 95% CI 1.1 to 2.2) compared with the patients who had N2 and LNR1 disease. Conclusion: LNR define breast cancer prognosis more adequate than the pN categories especially high risk breast cancer like young age, her2/neu enriched and triple negative intrinsic subtype. It is more reasonable that treatment decision like radiotherapy might be depend on the LNR than pN staging. We argue that LNR should be considered as an alternative to pN staging.
Figures available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-08.
Abstract P1-01-09: Molecular Detection of Sentinel Lymph Node Metastases in Breast Cancer Patients: Correlation between Cytokeratin 19 mRNA Copy Number Detected by One Step Nucleic Acid Amplification (OSNA) and Risk of Metastases in Axillary Lymph Nodes
Authors: Buglioni S , Casini B , Marandino F , Terrenato I , Gallo E , Perri P , Botti C , Maini CL , Di Filippo F. 
Published: April 2011

Abstract
Background: The accuracy of the OSNA assay for metastases detection in sentinel lymph nodes (SLNs) has recently been validated in our Institute and adopted as an intra-operative test for breast cancer (BC) patient management. The aims of this study in a series of early BC patients, were: 1) to correlate the copy numbers of cytokeratin 19 (CK19) mRNA with the size of nodal metastases and with the risk of additional disease in non-sentinel lymph nodes (NSLNs); 2) to investigate the relationship between SLN status with OSNA method, and conventional bio-pathological factors taking into account the molecular BC classification: luminal A, luminal B, HER2 subtype, and triple-negative; 3) to identify a subgroup of patients with positive SLN with higher risk of NSLNs metastatic involvement. Material and Methods: 750 SLNs from 580 patients were clinically processed using both OSNA assay and post-operative histology. The results of these two methods were then compared. The correlation between the size of metastases and the copy numbers of CK19 mRNA was calculated using the Spearman correlation coefficient. Complementary axillary lymph node dissection (ALND) was performed concurrently in case of OSNA assay positivity and the probability of having a positive lymph node axillary dissection was calculated by the unconditional logistic regression model. This series of BC patients were divided into four main subtypes taking in account the BC classification based on the immunohistochemistry phenotypic patterns.
Results: OSNA positivity was reported in 24.6% of the patients for a sensitivity of 94.2%. Considering the 145 patients with SLN positivity the size of metastatic foci was significantly correlated to the copy numbers of CK19 mRNA. The complex relationships among the bio-pathological variables analyzed by multiple correspondence analysis (MCA) showed that the metastatic involvement of NSLNs is associated with SLNs with a high copy numbers of CK19 mRNA and HER2 subtype tumors. OSNA specificity (95%) and negative predictive value (98.4%) clearly demonstrated its reliability to guide ALND decision. Conclusions: Our results showed that OSNA is an excellent method for the detection of metastases in SLN and its adoption in our clinical practice has determined a significant improvement in the diagnosis of metastatic BC.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-09.
Abstract P1-01-12: A Novel Method for Sentinel Lymph Node Biopsy by Indocyanine Green Fluorescence Technique in Breast Cancer
Authors: Sugie T , Kassim KA , Takeuchi M , Hashimoto T , Yamagami K , Masai Y , Toi M. 
Published: April 2011

Abstract
Background: Sentinel lymph node (SLN) biopsy is the standard method to assess the actual axillary lymph node status in breast cancer. Currently dye techniques, radioisotope techniques or combined techniques are usually used for SLN detection. Recently, near infrared fluorescence imaging has been applied clinically in a breast cancer patient to identify SLN. In this study, the feasibility of SLN biopsy using the indocyanine green (ICG) technique were evaluated.
Methods: The study involved four hundreds eleven patients with clinically node negative early breast cancer who underwent SLN in three institutes. A combination of ICG as a fluorescence emitting source and blue dyes were injected in the subareolar area and lymphatic flows were traced with a charge coupled device camera and a real-time image guided surgery enabled to identify the fluorescence image of SLN after meticulous dissection.
Results: The subcutaneous lymphatic channels were detected precisely in all cases. The identification rate of SLN was 99%, (408/411) with a mean number of 2.3±1.2 (range, 1-9) nodes identified per patient. Only one SLN harvested in 30.1% of patients, two in 29.4%, three in 23.9% and four or more in 15.9% of patients. Thirty nine cases (9.5%) had SLNs involved and all of them were ICG positive and 30 of 39 patients (77%) had one SLN involved.
Conclusions: This ICG fluorescence method is simple and achieves a high SLN identification rate. This technique does not require a facility equipped to use radioisotopes. This means that SLN biopsies could even be performed in a small hospital. Orderly and sequential dissection along the lymphatic flow may provide higher sensitivity compared with the conventional radioisotope method. A direct comparison between the radioisotope and ICG fluorescence methods is now required.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-12.