bluuebunny/crossref_metadata_2025 huggingface dataset:
Are There Groups of Patients Who Don't Benefit from Chemotherapy?
Authors: Ravdin P.
Published: December 2010

The obvious answer to this question is: Yes. There are two reasons that a medical therapy would not be considered as of benefit to patients. The first of these is that the risks of toxicity or negative effects of a therapy outweigh the benefits. The second is that that therapy does not work: that it does not decrease the risk of negative outcome (for breast cancer that the risk of recurrence and/or death). Over the last 10 years there have been improvements in how we can assess patients for the appropriateness of chemotherapy: 1) We can better predict patients' prognoses without therapy, 2) in a modest way we can better assess their risk for toxicity and 3)we can better predict for individual patients the relative efficacy of a therapy. Over the last decade models to that integrate classical pathologic information to better predict the prognosis of patients have been refined. An advance beyond these models is the development of multi-gene assays either dependent on evaluation of mRNA or proteins that can stratify patients into prognostic groupings. These new methods can be integrated with classical pathologic information to evaluate prognosis. Work on predicting toxicity from chemotherapy has been more modest, but have important possible application. Models exist for some chemotherapeutic regimens for predicting the risk of clinically significant neutropenia or cardiac toxicity. In some instances the risk of particularly severe toxicity to specific agents such as 5FU can be tested for. Perhaps the greatest advance during this period is the better definition of predictors of response to chemotherapy. There has been a long recognition that the estrogen receptor status can stratify patients particularly likely to benefit from chemotherapy, but new predictors are able to identify patients within ER subgroups with particular chemosensitivity. The move toward more personalized therapy is taking place with improvements in prognostic assessment of patients, their risk of toxicity, and whether specific agents will (or will not) reduce the risk of recurrence or breast cancer related death. This review will show that there are certainly are patients who can be identified who do not benefit from chemotherapy, and will in its summary examine what current treatment guidelines say on this topic

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr CS1-1.
Advances in Preventive Therapy.
Authors: Cuzick J.
Published: December 2010

Recent evidence on the chemoprevention of breast cancer has come from a number of sources: 1) Recent data on a new SERM – lasofoxifene – suggests this might be an attractive option, but further details are needed to fully evaluate its role. 2) Update on the tamoxifen and raloxifene preventive trials have shown a continued benefit after treatment completion, and an overview is ongoing to combine all the post-treatment data on risks and benefits. 3) Simple biomarkers for the preventive effect of tamoxifen have been reported. These include both genetic markers such as 2D6 polymorphisms and the observation that 12-18 month changes in breast density are predicative of the subsequent preventive benefit of this drug. A report from the ATAC trial indicating that the occurrence of endocrine symptoms predicts response to both tamoxifen and anastrozole may also have relevance in the preventive setting. 4) Long term follow-up of the adjuvant trials using aromatase trials has provided new evidence on the duration of a potential preventive effect by looking at isolated new contralateral tumours. This has been an excellent model for tamoxifen and may well also be so for the AIs. 5) New data confirm the long term protective effect of aspirin on breast cancer, but suggests it needs to be taken for at least 10 years to get a benefit. Mixed data have appeared for the statins. These issues will be reviewed and discussed.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr ES2-1.
Overview of Gene Expression Profiling and Novel Translational Technologies in Breast Cancer.
Authors: Perou C.
Published: December 2010

Gene expression profiling has had an enormous impact on many aspects of breast cancer, including elucidation of the basic mechanisms of carcinogenesis and mammary development, prediction of outcome and response to treatment, and identification of new subtypes of disease. Importantly, gene expression profiling in breast cancer has allowed the development of biomarkers that are being used in the clinic and/or will become part of routine clinical care in the near future. Genomic profiling is accomplished nowadays by using genome-wide DNA microarray assays, which evaluate thousands of genes with relatively low sensitivity, or qRT-PCR assays, which evaluate small numbers of genes with high sensitivity. The majority of these assays focus on mRNA molecules; however, in recent years, DNA microarrays evaluating other functionally important classes of RNA molecules, such as microRNAs and non-coding RNAs, have been developed and will likely have an impact on our understanding of breast cancer biology. Nonetheless, DNA microarrays and qRT-PCR assays based on mRNA have provided robust platforms for the investigation of breast cancer transcriptomes, and each has resulted in the development of clinically useful prognostic tests (i.e. OncotypeDX and Mammaprint). However, as with all technologies, new methods and platforms are constantly being developed, offering higher speed, lower cost and increased accuracy. Importantly, many of these promising new technologies are compatible with RNA derived from archival formalin-fixed paraffin embedded materials. Therefore, it is likely that gene expression-based assays will continue to play a critical role in the development of novel biomarkers, and the discovery of new targets. In this session, we will cover the basics of DNA microarrays and microarray statistics, and discuss the next generation of technologies to further study the gene expression patterns of breast cancers.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr ES3-1.
Sequencing of Breast Cancer Genomes.
Authors: Stratton M.
Published: December 2010

All cancer genomes carry somatic mutations. The recent advent of second generation sequencing technologies has brought closer the prospect of sequencing large numbers of cancer genomes. Early studies in breast cancer have investigated the prevalence and nature of rearrangements. These studies have shown that there are many more rearrangements in breast cancer than have previously been appreciated, some of which have distinctive patterns suggesting underlying DNA repair defects. These studies are now leading into the sequencing of complete breast cancer genomes which aim to generate comprehensive catalogues of somatic mutations. These will include point mutations, rearrangements and copy number changes and most of the driver and passenger mutations operative in individual cancers.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr ES3-2.
DNA Methylation – Role in Gene Regulation and Detection Methods.
Authors: Sukumar S.
Published: December 2010

Alteration in the epigenome, which includes DNA methylation, is by far, the most frequent cancer-specific event, and likely one of the earliest in the process of carcinogenesis. Human tumors display global hypomethylation, but selective hypermethylation occurs in the promoters of growth and tumor suppressor genes, which leads to subsequent silencing of gene expression. In addition to protein coding genes, this epigenetic control is exercised in the case of microRNAs as well. DNA methylation acts in concert with histone modifications to achieve an open or closed chromatin conformation that is conducive to gene transcription or silencing respectively. Methylation of DNA takes place at cytosine residues of CpG dinucleotides. When it occurs at multiple CpG dinucleotides (CpG islands) present in the promoter region of the gene, silencing of gene expression can ensue. The current state of knowledge regarding the components of this complex but reversible machinery will be discussed. Tumor specific methylation of genes and microRNAs has been reported in all types of liquid and solid tumors. Thus, tumor specific gene methylation has provided an embarrassment of riches as potential markers for risk assessment, early detection, predictive markers for drug susceptibility, and for predicting response to therapy. The ability to pharmacologically reverse epigenetic silencing of gene expression has resulted in the identification of number of drugs with great potential for treating all types of cancers. How does one detect methylation in DNA? The study of DNA methylation was revolutionized by the development of PCR and methods that rely on base changes brought about by treatment of DNA with sodium bisulfite. Recently, other methods have relied on separation of DNA using antibodies that recognize methylated DNA. These analyses are performed on a selected panel of genes or aim to determine the global methylation profile of a specific subset of cells in a tissue. A major challenge in the clinic is the application of these methods to very small clinical samples such as single biopsy sections, or microliters of body fluids while retaining a high level of sensitivity and specificity. These methods will be discussed, presenting advantages and disadvantages of each.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr ES4-1.
Diagnostic and Therapeutic Applications of Nanotechnology.
Authors: West J.
Published: December 2010

The increasing capability to manipulate matter at the nanoscale is generating new materials with unique properties that promise to address unmet medical needs for future generations. As an example, metal nanoshells are a relatively new class of nanoparticles with highly tunable optical properties. Metal nanoshells consist of a dielectric core nanoparticle such as silica surrounded by an ultrathin metal shell, usually composed of gold for biomedical applications. Depending on the size and composition of each layer of the nanoshell, particles can be designed to either absorb or scatter light over much of the visible and infrared regions of the electromagnetic spectrum, including the near infrared region where penetration of light through tissue is maximal. These particles are also easily conjugated to antibodies and other biomolecules for specific targeting. Further, the biocompatibility of these particles is excellent. One can envision a myriad of potential applications of such tunable particles. Several potential biomedical applications are under development, including immunoassays, modulated drug delivery, photothermal cancer therapy, and imaging contrast agents. For example, in photothermal cancer therapy, nanoshells can be injected intravenously, accumulate at tumor sites due to the enhanced permeability and retention (EPR) effect and/or molecular targeting, then generate heat upon illumination with near infrared light, leading to destruction of the tumor. This has shown very promising results in several animal models. For example, in a mouse colon carcinoma model, we demonstrated 100% survival of nanoshell treated mice at 1 year. These materials are now in phase I human clinical trials. For use in diagnostics and imaging, nanoshells can be designed to strongly scatter near infrared light. Molecularly targeted nanoshells have been used as optical contrast agents for cancer imaging with sub-cellular resolution. For example, anti-HER2 conjugated nanoshells allow near infrared imaging of HER2+ breast carcinoma cells. Furthermore, integrated imaging and therapy applications have been accomplished with nanoshells designed to provide both absorption and scattering, potentially enabling “see-and-treat” approaches to cancer therapy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr MS1-1.
International Breast Cancer Research: Launching an Expedition to the Moon.
Authors: Piccart M.
Published: December 2010

In his State of the Union address in 1971, President Nixon launched a "war on cancer" by calling for the "same kind of concentrated effort that split the atom and took man to the moon" to be turned towards conquering cancer. Since this landmark address, great strides have been made in the war on breast cancer. Lumpectomy with adjuvant radiotherapy, sentinel lymph node dissection, and adjuvant systemic therapy in the form of chemotherapy, hormonal therapy and trastuzumab have improved the quality of life and long-term survival of women diagnosed with early breast cancer. International collaboration involving research groups and initiatives such as the Early Breast Cancer Trialists' Collaborative Group quinquennial overviews has provided the clinical trials infrastructure and framework necessary to synthesize the evidence-based data upon which these gains have been achieved. Despite these successes, the pathway to new drug development and improved medical effectiveness today is costly, labor-intensive, and far too slow for our patients. Over the last decade, the advent of molecular technologies has dramatically improved our understanding of the biology of breast cancer. We now have targeted therapies available to inhibit specific signaling pathways that are aberrant in subpopulations of breast cancer. To further improve breast cancer care, we must fundamentally rethink how translational research is performed in clinical trials. The challenge of making personalized medicine a reality demands the launch of an expedition taking us to and beyond the moon: it will involve clinicians, basic scientists, bioinformaticians, statisticians, industry sponsors, regulators, and patients in new partnership that is committed to changing the vision, culture and methodology of breast cancer research. The Breast International Group's efforts in this direction will be presented.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr W1-1.
Assessment of the performance of the Stanford online calculator for the prediction of non-sentinel lymph node metastasis in sentinel node positive breast cancer patients.
Authors: Scow JS , Degnim AC , Hoskin TL , Reynolds C , Boughey JC
Published: December 2010

Abstract #1005

Background: Several models for the prediction of non-sentinel lymph node metastasis (+NSLN) in sentinel lymph node positive (+SLN) breast cancer patients have been published. Multiple variables have been shown to be important in prediction of +NSLN. To this date, models that utilize 7-8 variables have been significantly more discriminatory than models using only 2-3 variables. In this study, we evaluate the performance of the newly created Stanford online calculator (SOC) to predict the likelihood of +NSLN. The SOC uses 3 variables: primary tumor size, sentinel lymph node metastasis size, and presence/absence of lymphovascular invasion.  Methods: From 1997-2004, 465 breast cancer patients with clinically negative axillae were found to have a +SLN and underwent completion axillary lymph node dissection (ALND) at the Mayo Clinic. Using the SOC the probability of having +NSLN was determined for each patient. Complete variable data was available for 464 patients which make up the cohort reported here. A receiver-operating characteristic (ROC) curve was created and the area-under-the-curve (AUC) was calculated. Mean probabilities of patients with and without +NSLN were compared. Additionally, patients with a low Stanford probability were examined to determine the model's accuracy in discriminating patients who could potentially be spared ALND. These results were compared to the results of the Mayo Clinic and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms which have been previously applied to this same cohort of patients.  Results: The AUC of the Stanford model was 0.72 (95% CI 0.67-0.77). The mean Stanford probabilities for patients with and without NSLN disease were 0.75 (range 0.06 to 1.0) and 0.50 (range 0.05 to 1.0), respectively (p < 0.0001). Examining patients with a Stanford probability <= 10%, we found that 47 patients met this criterion; 6 had +NSLN and 41 did not, for a false negative (FN) prediction rate of 13%. There was only 1 patient with Stanford probability <= 5%, and this patient did not have +NSLN. The AUC of the MSKCC and Mayo nomograms in this same patient population was 0.74 and 0.77, respectively. The AUCs did not differ significantly (p = 0.13) among the 3 models.    Conclusion: Despite using only three variables, the Stanford nomogram appears to perform as well as, but not better than the MSKCC and Mayo nomograms in our patient cohort. Further validation in other patient populations is needed prior to widespread utilization of this nomogram.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1005.
Technical aspects of the sentinel node biopsy in the EORTC AMAROS sentinel node trial.
Authors: Straver ME , Meijnen P , van Tienhoven G , van de Velde CJ , Mansel RE , Bogaerts J , Demonty G , Rutgers EJ
Published: December 2010

Abstract #1006

Background: The AMAROS trial is a phase III study comparing axillary lymph node dissection (ALND) with axillary radiation therapy (ART) in patients with proven axillary metastasis by sentinel node biopsy (SNB). The main objective of the trial is to prove equivalent locoregional control and reduced morbidity for ART. The aim of this interim analysis was to analyze the technical aspects of the SNB.  Methods: The first 2000 patients with operable unifocal invasive breast cancer (5-30 mm) and clinically negative lymph nodes enrolled in the AMAROS trial between 2001 and 2005 were analyzed. The 26 participating institutions have been site visited as part of the surgical quality assurance. SNB is performed using preoperative lymphoscintigraphy, blue dye and a gamma-ray detection probe. Patients with a negative sentinel node were not subjected to ALND or ART.  Results: The SN identification rate was 97% (range per institute 89%- 99%), 33% (n=658) of the patients were SNB positive, 62% (n=1245) were SNB negative and 2%(n=32) had other outcomes (non-axillary, missing data). Median two sentinel nodes were removed in the SNB positive as well as the SNB negative group. In 17% (344) of the patients, non-blue and non radio-active nodes were removed during the sentinel node procedure, median 1 node. In 11 patients, these nodes were the only tumor positive nodes found. In the SNB positive group the incidence of macro-, micrometastasis and isolated tumor cells was 61% (389), 26% (164) and 13% (80), respectively. In the ALND arm, further nodal involvement was seen 47,5% , 21,4 % and 16,7%, respectively. There was no correlation between the size of metastasis and the tumor size, grade or histological subtype. Of the sentinel nodes 59% (1907/3259) were radioactive and blue, 33% (1087/3259) were only radioactive, 8 %(265/3259) were only blue. Non-visualization on lymphoscintigraphy was seen in 7.6%(152), in 78%(118) of these cases a sentinel node was found during surgery. At least one sentinel node was located in the axilla in 89%(1777), in the internal mammary chain in 5% (104) and infra/supraclavicular in 1%(15). The injection site was intra/peritumoral in 53% subcutane/intradermal over the tumor in 9% periareolair in 16%, a combination in 4%, missing data 17%. Sentinel nodes in the internal mammary chain were significantly correlated with a intratumoral injection technique.  Conclusions: These results indicate that with a 97% detection rate in this prospective international multicenter study using the combination of radioactive tracer and blue dye, the sentinel node procedure is highly effective. Differences in injection site affect the finding of non axillary sentinel nodes.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1006.
Intra-operative touch imprint cytology for assessing sentinel lymph nodes in patients with lobular breast cancer.
Authors: Fazel MZ , Gogalniceanu P , Patel A , Capitano A , Kocjan G , Falzon M , Douek M
Published: December 2010

Abstract #1008

Background: Touch imprint cytology (TIC) as a tool for intra-operative assessment of sentinel lymph nodes (SLN) in breast cancer has been shown to be rapid, reliable and cost-effective. Its use in lobular cancer is however more challenging due to the pattern of lymph node infiltration, smaller cells, similarity to lymphocytes and low grade cytomorphology. The aim of this study was to evaluate the sensitivity and specificity of intra-operative TIC in assessing SLN metastases in patients with lobular breast cancer.  Material and Methods: All patients with lobular carcinoma who underwent intra-operative TIC assessment of the SLN were identified within our prospectively collected database. The SLN was bi-valved along its longitudinal axis and imprinted onto a slide at least six times before air-drying. The slide was treated with the rapid Giemsa stain before examination by one of three cytopathologists. Where TIC revealed SLN metastases, the patient underwent immediate axillary clearance. The SLN were then processed for histopathology by sectioning at three levels before haematoxylin and eosin staining. Those lymph nodes found to be negative then underwent immunocytohistochemistry staining before being declared truly negative. All patients with SLN metastases not identified during surgery received a delayed axillary clearance. The TIC results were compared to the final histopathology result of the SLN and the sensitivity and specificity calculated.  Results: 51 patients with lobular cancer who underwent TIC were identified. The table below summarises the results:    The sensitivity thus calculated was 76.0%; the specificity 100.0% and the negative predictive value 81.25%. Of the 6 false negative cases, 4 were grade 1 and 2 were grade 2. The mean primary tumour size in this group was 17mm (range 11 to 27mm). In all 6 cases, axillary metastases was found in 3 or fewer lymph nodes post axillary clearance.  Discussion: This study demonstrates the reliability of using intra-operative TIC to evaluate SLN during surgery for lobular cancer. It compares very favourably to data published in the literature from other institutions that have examined the use of TIC in lobular carcinoma and may relate to the presence of experienced, highly motivated cytopathologists at our unit. In addition, it also compares well with other studies describing the use of TIC in ductal carcinoma, including our own unit's previously published data. Thus, in experienced hands, TIC is feasible with an acceptable accuracy allowing intra-operative SLN assessment in patients with lobular breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1008.
The significance of intramammary lymph node metastases in breast cancer management.
Authors: Hogan BV , Peter MB , Shenoy HG , Horgan KM , Shaaban AM
Published: December 2010

Abstract #1009

Introduction   Intramammary lymph nodes are defined as lymph nodes surrounded by breast tissue. They are a potential site of regional spread for breast cancer and metastases in this node is reported in up to 9.8% of operable breast cancers. Despite this, the existence of the intramammary node is not widely appreciated and the clinical significance of intramammary nodal metastases remains uncertain. The aim of this study is to determine the prognostic relevance of intramammary lymph node metastases and how it impacts on current breast cancer treatment modalities.  Methods  All patients with cytologically or histologically proven intramammary nodes were identified from the pathology database at the Leeds Teaching Hospitals. A total of 102 specimens were identified in 100 patients with a primary breast malignancy over a 13 year period (1994-2007). Clinical data including information on recurrences and death was obtained from patient records.  Results  One hundred patients were identified on our pathology database to have intramammary lymph nodes in association with a primary breast cancer. Ten were identified pre-operatively on breast imaging and 90 were first discovered on pathological assessment of excised breast tissue. Twenty one contained metastases. Factors that predicted for intramammary node metastases were lymphovascular invasion (p=0.002) and grade of tumour (p=0.012). The presence of metastases within the intramammary lymph node was associated with a poorer disease free survival (p=0.0072) and reduced overall survival (p=0.0128) at a mean follow up of 34.7 months. Sixty seven percent of patients with intramammary node metastases had further axillary metastases. In no case was the intramammary node identified as the sentinel node. One patient had an intramammary node metastases but benign axillary sentinel node. An axillary node clearance was not performed and she presented 19 months later with an axillary nodal recurrence.  Conclusion  The presence of intramammary lymph node metastases is associated with poorer outcome in breast cancer patients. Pre-operative detection of intramammary lymph node metastases is helpful to guide breast and axillary surgery. With the use of lymphoscintigraphy intramammary nodes will be increasingly identified as the sentinel node. Intramammary lymph node metastases predicts strongly for axillary metastatic disease and axillary node clearance should be recommended even when it is associated with a benign axillary sentinel node biopsy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1009.
Predicting the burden of axillary disease in breast cancer patients with a positive sentinel node.
Authors: Unal B , Gur SA , Beriwal S , Johnson R , Ahrendt G , Bonaventura M , Soran A
Published: December 2010

Abstract #1010

Background: Current practice is to perform a completion axillary lymph node dissection (ALND) for breast cancer (BC) patients with tumor-positive sentinel lymph nodes (SLNs). However, not all patients with positive SLNs have further ALND. Katz et al suggested a nomogram for predicting having four or more positive nodes for SLN-positive BC which could change the adjuvant radiation treatment fields. Our goal is to validate the accuracy in predicting > 4 positive axillary lymph nodes in BC patients with a positive SLN in our institution. Methods: Katz nomogram was developed from the multivariate logistic regression model using tumor histology, primary tumor size, lymphovascular space invasion, extranodal extension, the number of involved SLNs, the number of uninvolved SLNs, and the size of the largest SLN metastasis. Area Under (AUC) Receiver Operating Characteristics Curve (ROC) was calculated for the nomogram and a value more than 0.70 was accepted as providing considerable discrimination. Results: We reviewed the records of 319 patients with invasive BC and positive SLNs who underwent completion ALND at MWH of UPMC. None of these patients received neoadjuvant chemotherapy The mean age was 54.2 (30-84) years. Eighty-nine patients (27.8%) had four or more positive nodes. Histology was invasive ductal carcinoma for 86.2 % of patients. The median tumor size was 2.22 (0.5-8.0) cm. Seventy percent of patients had only one involved SLN. The median size of the largest SLN metastasis on H&E staining was 9.7 mm (range, < 0.2 to 35 mm), and 24.4% of the patients had micrometastases (2 mm). Ninety nine patients (31%) had extranodal extension. The mean predicted probability of having ≥ 4 involved axillary LNs was 31.9 % (range, 1 to 99) in patients with ≥ 4 involved axillary LNs while it was it is 9.1% (range, 0.5 to 80) in patients having < 4 axillary LN metastases (P<0.001). The AUC value was 0.809. Conclusions: The Katz nomogram developed to predict having ≥ 4 involved axillary lymph nodes in BC patients with a positive SLNs is validated in our patients. Nomograms developed at other institutions should be used with caution when counseling patients regarding the risk of additional nodal disease. This nomogram will be helpful to clinicians making adjuvant treatment recommendations in practice.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1010.
Cost utility analysis on one-step nucleic acid amplification method for the detection of axillary metastasis in breast cancer.
Authors: Nishimura K , Sugiyama D , Moronobu A , Kawano S , Kumagai S
Published: December 2010

Abstract #1014

Back ground :OSNA method, One-step Nucleic Acid Amplification(OSNA) method is a new method for rapid detection of axillary lymph node metastases of breast cancer using PCR to detect cytokeratin 19's mRNA and different from conventional hsitopathological examination. It can be automated and can detect the axillary lymph node metastases quickly and precisely during operation. No cost effectiveness studies are conducted for this method.  Materials and Method: We conducted the cost effectiveness analysis for this method comparing with conventional hsitopathological method using Markov models. We adopted the societal perspectives and the time horizon for fives years. We used TreeAge Pro 2005 (TreeAge Software Inc, Williamsontown, MA) to conduct Markov simulations. One way sensitivities analysis were conducted for all parameters. Cost and utilities data were collected from the studies and clinical trials for OSNA and conventional methods.  Results: When the cost of OSNA is assumed as the same as intra-operative lymph node diagnosis by histopathology, the Markov model has shown the cost saving of $11,527/QALY by OSNA method. When the sensitivity analysis was performed by changing the cost of OSNA, the result has shown that OSNA can still show cost saving until the cost of OSNA method is $1,094 higher than the hsitopathological examination. Discussion: Our results clearly revealed OSNA methods is cost saving compared with convention intraoperative hsitopathological examinations. Result is robust for all parameters included in the model. Since OSNA method can avoid unnecessary re operations for axillary lymphadenectomy, this method can improve the quality of life for breast cancer patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1014.
Prognostic significance of sentinel nodes metastases in breast cancer patients without axillary node dissection or axillary radiotherapy: CBCSG-001 trial.
Authors: Wang Y , Wang C , Fan L , Mu D , Gao Y , Li J , Zhong W
Published: December 2010

Abstract #1015

Background: China multicenter study of sentinel lymph node biopsy (SLNB) substituting axillary lymph node dissection (ALND) in breast cancer– CBCSG-001 trial was conducted from Jan. 2002 to Jun. 2007, with 1,970 SLNB pts recruitment. One of the second objectives of the CBCSG–001 trial was to evaluate the optimal methods and intervals for the detection of SLN macrometastases, MMs and isolated tumor cells (ITCs) and their prognostic significance in patients received SLNB without ALND or axillary radiotherapy.  Material and Methods: Two hundred and forty-five continuous breast cancer patients with 569 SLNs identified “negative” with routine standard HE stain carried on initial 4 levels were retrospectively analyzed. All the patients received SLNB only, without ALND or axillary radiotherapy after the diagnoses of metastases in their SLNs later. All SLNs were step sectioned (SS) at 100µm interval, and for each level both HE and IHC with AE1/AE3 were performed. Forty-nine patients were identified to have metastases, with macrometastases of 12.2%, micrometastases of 61.2%, and isolated tumor cells of 26.5%. All patients had received SLNB only, with no ALND and axillary radiotherapy.  Results: Of the 245 patients, breast conserved surgery and SLNB were performed on 106 patients (43.3%), and mastectomy and SLNB in 139 patients. With a median follow up of 50 months, there were 20 breast related events occurred. The disease free survival (DFS) of patients with routine negative SLNs was 91.6%, and 93.9% for patients with positive SLNs after SS with HE+IHC (p>0.05). The overall survival (OS) were 97.4% and 98.0 for each group, respectively (p>0.05). The results were the same for patients with macrometastases, micrometastases, and isolated tumor cells. Due to the relatively less events occurred, the DFS and OS had not been calculated for macrometastases, micrometastases, and isolated tumor cells, separately.  Discussion and Conclusions: Without ALND and axillary radiotherapy, there were no significant differences of DFS and OS between patients with routine negative SLNs and patients with positive SLNs after SS with HE+IHC. It might be safe for these patients to receive SLNB only. The possible reasons might include: SLNs were the only positive lymph nodes in more than 60% patients, effective adjuvant systemic therapy for regional lymph nodes just as neoadjuvant chemotherapy, axillary coverage of radiotherapy in patients with breast conserved therapy, and the relatively less events occurred during the 50 months follow up period.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1015.
Intraoperative training on the techniques of sentinel node biopsy in breast cancer.
Authors: Delaloye JF , Pampallona S , Cuchard P , Monod JF , Brunisholz Y
Published: December 2010

Abstract #1016

Background: Sentinel node biopsy (SNB) is an accurate procedure for axillary staging and the surgeons' experience is crucial for its proper application. A training session involving 20-30 cases is widely practiced. In order to speed up this learning curve, surgeons were trained intraoperatively by one instructor. The purpose of this report was to evaluate the procedure by comparing the results of the instructor with those of the trainees.  Material and Methods: Patients with invasive breast cancer (T0-T2[<3cm]N0M0) were considered eligible. Lymphatic mapping was obtained by peritumoral or periareolar injections of technetium with or without blue dye. Complementary axillary lymph node (LN) dissection was performed when SNB was unsuccessful or when SN were positive. Patients were distributed in 4 groups : (i) teacher's learning curve (SNB followed by complementary axillary dissection) (n=40), (ii) SNB by instructor (n=130), (iii) SNB by trainees with supervision from instructor (n=63), and (iv) SNB by trainees alone (n=303). The criteria of patients' selection, the parameters of success of the SNB procedure, and the LN metastases were compared. Reported p-values compare groups (ii) to (iv).  Results : From May 1999 to December 2007, 808 patients underwent a SNB. The SN identification rate was 98% in the group (i), 98% in the group (ii), 97% in the group (iii), and 99% in the group (iv) (p=0.196). SN were positive in respectively 28%, 31%, 28%, and 29% of patients. Overall positive nodes (SN and LN) were diagnosed in respectively 28%, 31%, 30%, and 30% of patients (p=0.833). The distribution of isolated tumor cells, micrometastases, and metastases was not statistically different between the four groups (p=0.163).  Conclusion: These comparable results confirm the success with which the SNB was taught. This strategy avoided the 20-30 SNB with complementary axillary dissection.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1016.
A new hand-held gamma camera for sentinel node detection in breast cancer. The Minicam experience in 50 cases.
Authors: Garbay J , Ricard M , Lumbroso J , Rimareix F , Uzan C , Gouy S , Leroy P
Published: December 2010

Abstract #1021

Background: The Minicam* is a high-resolution 1.6 inches field-of-view hand-held gamma camera. We used it to detect breast cancer sentinel nodes (SN).  Material and Methods : This is a prospective, non-randomized, blind study comparing the minicam (MC) and classic scintigraphy (CS) in 50 cases. All patients underwent CS, and the surgeon used the MC in the operating room blinded to the CS results. Then CS images were visualized and the operation was performed as usual with a probe. At the end of the procedure, control MC images were obtained and displayed.  Results : Isotopic detection failed in a single case (1/50). Concordance between the MC and CS was very good in 33 cases (67.5%). In 6 cases (12%), the MC was better and in 10 cases (20.5%) CS was better, in terms of the number of detected nodes. The post-procedure control images were always negative. The surgeon found that the MC was better than the probe for node localization in 2 difficult cases. It took 4 to 10 minutes using the MC in the first 8 cases, and a mean of 2 minutes (range 1-3 min) thereafter. The small screen size (1.6x1.6 inches) was noted as the cause of difficulties in 12 cases and was associated with 4/10 failures.  Discussion : This minicam device is easy to use for the surgeon, with a user-friendly software, a short learning curve and good accuracy. The small screen size is really the only drawback. On the basis of this first blind comparison with CS, a larger multicentric study will be initiated.  * Euromedical, France.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1021.
Correlation between pN0(mol+) and standard clinico-pathological prognostic factors in SLN of breast cancer patients.
Authors: Varela M , Moreno A , Falo C , Villalba E , Benito E , Serra J , Fernández A , Escobedo AP
Published: December 2010

Abstract #1025

Objective: To establish the significance of disease detected by reverse transcription polymerase reaction (RT-PCR) in sentinel lymph nodes (SLN) of breast cancer patients.  Background: In breast cancer patients, the axillary status is the most important prognostic factor. The RT-PCR appeared to be a sensitive method, but the relevance of pN0(mol+) has not yet been established.  Methods: 674 patients with T1-T3 primary invasive breast cancer were included in a prospective study. SLN were analysed by routine pathology analysis (staging with hematoxylin-eosin – H&E– and immunohistochemistry – IHQ–) and RT-PCR. Correlations between molecular diagnostics and standard clinicopathological prognostic factors, including St. Gallen risk categories were analyzed.  Results:  Of the 674 patients, 131 (19.4%) had one or more pathology-positive SLN detected by routine pathological, 137 (20.3%) were exclusive molecular positive - pN0 (mol+) - and 406 (60.2%) were without evidence of disease.  We evaluated correlation between nodal staging with pathological and molecular analysis and clinicopathological factors in the whole patient cohort. Positive cases were significantly associated with tumor size (p<0.010), histological grade (I-II vs. III) (p<0.048), vascular invasion (p<0.000) and St. Gallen risk category (p<0.003).  Conclusions: molecular staging of SLN using RT-PCR could serve as a useful complement to standard clinico-pathological risk factors. Correlation between pN0(mol+) patient group with survival rates will define the clinical relevance of lymph node molecular detected micrometastases in this patient population.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1025.
Efficacy of bevacizumab (BV) plus docetaxel (D) does not correlate with hypertension (HTN) or G-CSF use in patients (pts) with locally recurrent (LR) or metastatic breast cancer (mBC) in the AVADO phase III study.
Authors: Chan A , Vanlemmens L , Conte PF , Beith J , Samonigg H , Verma S , Srimuninnimit V , Martoni A , Miles DW
Published: December 2010

Abstract #1027

Background: BV (Avastin®), a monoclonal antibody to VEGF, significantly improved PFS and response rate in pts with LR or mBC when combined with 1st-line taxane CTx in two randomised phase III studies: E2100 (BV + weekly paclitaxel) and double-blind, PL-controlled study AVADO (two different BV doses + D). Efficacy of some biological agents correlates with certain toxicities. This was hypothesised for HTN with BV use and investigated in the AVADO study in an exploratory analysis. In contrast, CSF use in pts receiving CTx may adversely affect response, so correlation of G-CSF use with efficacy was also examined.  Methods: This study compared BV 7.5 or 15mg/kg + D 100mg/m2 with PL + D in 736 pts with inoperable LR or mBC with no CTx 6 months prior to randomisation (12 months if taxane-based), ECOG PS 0–1 and adequate LVEF. D was administered q3w for up to 9 cycles, BV/PL q3w until disease progression or unacceptable toxicity.  Results: The safety population consisted of 730 pts. Reported grade 3–4 HTN was low in the AVADO BV arms (1 pt, 0.4% [BV 7.5mg/kg]; 8 pts, 3.2% [BV 15mg/kg]), therefore the analysis of correlation with efficacy was performed for all grades of HTN. Data for HTN of all grades and G-CSF use in all randomised pts are shown below. Use of G-CSF did not affect dose intensity of D.    Conclusions: Efficacy of BV + D in pts with LR or mBC did not appear to correlate with incidence of all grade HTN or G-CSF use. The apparent PFS and response benefit in the BV 7.5mg/kg arm for pts with HTN should be taken with caution as it is based on a small number of pts and may be due to an imbalance in baseline characteristics or a higher likelihood of detecting HTN in patients receiving study therapy for longer. Analysis of a larger dataset is needed to provide further data in this context.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1027.
VEGF, VEGFR2 and HIF-1α expression in circulating tumor cells (CTCs) of breast cancer patients.
Authors: Kallergi G , Agelaki S , Gannoukaraki V , Markomanolaki H , Lianidou E , Mavroudis D , Georgoulias V
Published: December 2010

Abstract #1028

Background: Development of metastasis is associated with the presence of circulating (CTCs) and disseminated (DTCs) tumor cells in peripheral blood and bone marrow of breast cancer patients, respectively. Hypoxia and Vascular Endothelial Growth Factor (VEGF) play an important role in angiogenesis. There is no data published concerning the expression of HIF-1α and VEGF/VEGFR in CTCs. Methods: Double staining immunofluoresent experiments were designed to test the expression of VEGF, VEGFR and HIF-1α in CK (Cytokeratin)-positive CTCs from 34 metastatic breast cancer patients. PBMC cytospins were double stained with a monoclonal pancytokeratin antibody (A45-B/B3) along with each of the following: VEGF, VEGFR2 or HIF-1α polyclonal antibodies, respectively. Results: According to our experiments, CTCs from 62%, 47% and 76% of patients expressed VEGF, VEGFR2 and HIF-1α, respectively. In addition, VEGF, VEGFR2 and HIF-1α were expressed in 73%, 71% and 56% of the total number of examined CTCs, respectively. In 24% of the patients CTCs expressed all the investigated molecules. VEGF expression in CTCs was confirmed by performing RT-PCR with VEGF-specific primers in immunomagnetically-separated epithelial cells. Double and triple staining experiments and confocal microscopic analysis of immunomagnetically-isolated CTCs confirmed that VEGF was co-expressed with HIF-1α and VEGFR. Discussion: VEGF and VEGFR2 colocalization in CTCs indicate the presence of an autocrine loop in these cells. Our results demonstrate VEGF, VEGFR2 and HIF-1α expression in CTCs of patients with metastatic breast cancer and thus constitute the basis for using anti-angiogenic therapy for their elimination.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1028.
Populations of cells exhibiting epithelial-mesenchymal transition (EMT) or stem cell characteristics can be propagated from a single inflammatory breast cancer (IBC) cell line based on culture conditions.
Authors: Debeb BG , Hall CS , Xu W , Ueno NT , Reuben JM , Robertson F , Lucci A , Buchholz TA , Hortobagyi GN , Cristofanilli M , Woodward WA
Published: December 2010

Abstract #103

We have previously reported the isolation of a novel IBC cell line (MDA-IBC-1) from human pleural effusion fluid by passaging cells under 3-dimensional (3D) mammosphere (progenitor-promoting) conditions and isolating attached 2-dimensional (2D) cells from ultralow attachment plates. Mammosphere culture is serum-free and growth factor enriched. Serum-starving 2D cells leads to spontaneous formation of floating mammospheres with the same percentage of CD44+24- cells as 3D cultured mammospheres. 2D cells display distinct fibroblastic morphology. Here we report that passage in 2D (standard) or 3D (mammosphere) culture selects for different molecular phenotypes: EMT in 2D and stem/progenitor-like in 3D. 3D cells are generated from 2D cells for all experiments and are examined at second passage. RT-PCR reveals embryonic stem cell pluripotency factors Oct-4, Nanog, Sox-2 and Rex-1 are expressed in 3D but not 2D MDA-IBC-1 cells. MicroRNAs reported to be involved in self-renewal of breast cancer cells including Let-7a,b,c,d,e and f are decreased in 3D cultures (>5 fold decrease) compared to 2D. MiR16, 21, 125b and 200c are also markedly reduced in 3D vs. 2D cells. On the other hand, EMT proteins, N-cadherin, vimentin, and fibronectin are only expressed in 2D culture and higher expression of snail and slug is observed in 2D compared to 3D. Correspondingly, E-cadherin is absent from 2D cells. Moreover, Notch1, a putative stem cell signaling pathway protein that has been shown to promote EMT by snail induction is upregulated in 2D cells compared to 3D, and in response to radiation in both 2D and 3D. It has been reported in some systems that EMT promotion can induce stem cells. The data herein suggest the MDA-IBC-1 maintains pluripotent cells capable of both EMT and stem-like phenotypes. MDA-IBC-1 provides a unique model to examine the interaction between stem cells and EMT and to examine the mechanisms of resistance and proliferation of both cell types.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 103.
Safety of surgery in patients (pts) with locally recurrent (LR) or metastatic breast cancer (mBC) treated with docetaxel (D) plus bevacizumab (BV) or placebo (PL) in the AVADO phase III study.
Authors: Cortés J , Pivot X , Schneeweiss A , Wilcken N , Ellis P , Linderholm BK , Ribelles N , Clemens M , Haslbauer F , Miles DW
Published: December 2010

Abstract #1030

Background: The monoclonal antibody BV (Avastin®) specifically inhibits the biological activity of VEGF to disrupt tumour angiogenesis. The addition of BV to first-line taxane chemotherapy (CTx) increased clinical benefit in two randomised phase III studies of pts with LR or mBC, E2100 and AVADO. It is hypothesised that VEGF is essential for wound-healing, so it is recommended that BV therapy is interrupted prior to surgery and not restarted until the wound is fully healed. Incidence of wound-healing complications and bleeding events was investigated in pts undergoing surgery during the AVADO study.  Methods: Pts with HER2-negative, inoperable LR or mBC, no CTx 6 months prior to randomisation (12 months if taxane-based), ECOG PS 0–1, adequate LVEF were randomised to BV (7.5 or 15mg/kg q3w) + D (100mg/m2 q3w for ≤9 cycles) or PL + D until disease progression or unacceptable toxicity. Safety of BV was evaluated in pts undergoing surgery. Major surgery was defined as any surgery requiring opening of a body cavity or more than local anaesthesia.  Results: 42 surgical procedures were performed on the ITT population of 736 pts; ranging from minimally invasive procedures to major operations. The number of surgical events was similar in each study arm (PL: 17, BV 7.5mg/kg: 17, BV 15mg/kg: 8). Bleeding and wound-healing events reported in these pts after the date of surgery are presented below.    Conclusions: This is the first analysis of the safety of surgery in pts with LR or mBC receiving BV. Treatment with BV + D did not affect the number of pts undergoing surgery. No effect of BV therapy was seen on the frequency of grade 3–5 bleeding and wound-healing adverse events in these pts. BV therapy was interrupted for longer periods pre- and post-major surgery, which may explain why bleeding and wound-healing adverse events are not increased in pts undergoing these procedures. Larger studies are required to obtain a more accurate picture of the safety of surgery in advanced breast cancer pts treated with BV.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1030.