bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract ES3-3: Clinical Trial Designs for New Therapies: What Endpoints Should We Use?
Authors: Hudis CA 
Published: August 2014

Abstract
The selection of endpoints is critical to the interpretation of clinical trials results. In early phase clinical trials investigators seek evidence of activity, then predictors of clinical benefit, and in most randomized trials, accepted surrogates of meaningful benefit. At one extreme we may seek improvements in overall survival while in another we may be satisfied simply with evidence of tumor stabilization or changes in circulating biomarkers. In between these extremes are intermediate and composite endpoints including “partial responses”, “clinical benefit rate”, and those that are time-dependent endpoints such as disease-free or progression free survival. Many of the discussions and disagreements we hear in the context of drug development, benefit, and approval can be linked to a fundamental lack of agreement on the value and meaning of many of these endpoints. Activity of a given novel agent may, or may not, persuade some investigators, clinicians, and patients, that it is a worthwhile addition to our treatment options. On the other hand, a small but statistically significant improvement in overall survival in advanced cancer may, or may not, convince this same audience that the tested treatment is worthy of approval and use. Again, the intermediate endpoints may be unreliable or only weak predictors of more profound benefits. We will review and explore these issues considering not only the endpoints themselves but also their meaning in specific clinical settings and the impact of endpoint selection on further drug development.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES3-3.
Abstract ES7-2: Tumor Dormancy from an Experimental Biologist's Perspective
Authors: Chambers AF 
Published: August 2014

Abstract
Survival from breast cancer has improved steadily over the past decades. However, most breast cancer deaths are due to metastasis, and considerably less progress has been made against metastatic disease. We still know remarkably little about preventing or delaying metastatic recurrence or effectively treating the cancer if it does recur. Making breast cancer treatment even more challenging is the fact that breast cancer patients may appear to be cured of their disease, only to have it return later. These recurrences can happen even decades after apparently successful primary treatment. This creates years of uncertainty for breast cancer patients, who do not know if they have been cured or if the cancer will return, and makes clinical management difficult.
We have used experimental models, both in vitro and in vivo, to try to understand the process of breast cancer metastasis. We have found that a population of cancer cells can remain as dormant cells, and have shown that these cells can resist being killed by cytotoxic chemotherapy that successfully kills actively diving cells. Experimental studies raise questions that must be addressed clinically. For example, what is the prevalence of dormant cells in breast cancer patients – are they common or rare? Are there factors inherent to the cancer cells that influence the likelihood of dormant cells persisting and subsequently re-awakening? Conversely, are there host microenvironmental factors, such as diet, exercise or stress, that can influence whether dormant cells persist and re-awaken? This information will be important in learning better how to prevent, delay and treat metastatic breast cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES7-2.
Abstract MS1-1: Targeting PI3K
Authors: Cantley L , Lewis C. Cantley 
Published: August 2014

Abstract
Phosphoinositide 3-Kinase (PI3K) is a central enzyme in a signaling pathway that mediates cellular responses to growth factors. The signaling pathway downstream of PI3K is highly conserved from worms and flies to humans and genetic analysis of the pathway has revealed a conserved role in regulating glucose metabolism and cell growth. Mutational events that lead to hyperactivation of the PI3K pathway result in hamartoma syndromes and cancers. Activating mutations in PIK3CA, encoding the p110alpha catalytic subunit of PI3K (PIK3CA) or inactivating mutations in PTEN, a phosphoinositide 3-phosphatases that reverses the effects of PI3K, are among the most common events in solid tumors, especially breast cancers. Drugs that target PI3K are in clinical trials for a variety of cancers. It is likely that PI3K pathway inhibitors will need to be combined with other drugs to be broadly effective. We have employed genetically engineered mouse models that develop cancers due to mutations in genes in the PI3K pathway and are using these models to explore the efficacy of PI3K pathway inhibitors as single agents or in combination with other drugs. We are also interrogating the role of PI3K in the growth and survival of Brca1/p53 mutant breast cancers. The role of PI3K inhibitors for treating cancers in these mouse models and in human trials will be discussed.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr MS1-1.
Abstract P1-01-05: The Efficacy of Arm Node Preserving Surgery Using Axillary Reverse Mapping for Preventing Lymphedema in Patients with Breast Cancer: The results from a 2-year follow-up
Authors: Lee J-H , Son G-T , Choi J-E , Kang S-H , Lee S-J , Bae Y-K 
Published: August 2014

Abstract
Purpose: The axillary reverse mapping (ARM) technique to identify and preserve arm nodes during sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) was developed to prevent lymphedema. In our previous study, we evaluated the incidence of lymphedema after ARM and the difference in arm circumference between arm node preserved group and unpreserved group, after short term follow up. The purpose of this study was to investigate the location and metastatic rate of the arm node, and to evaluate the further follow-up results of the differences in arm circumference after arm node preserving surgery.
Methods: From January 2009 to December 2011, 116 breast cancer patients who underwent ARM were included. Blue-dye (2.5ml) was injected into the ipsilateral upper-inner arm. At least 20 minutes after injection, SLNB or ALND was performed and blue-stained arm nodes and/or lymphatics were identified. Patients were divided into two groups, an arm node preserved group (87 patients had ALND, 10 patients had SLNB) and an unpreserved group (15 patients had ALND, 4 patients had SLNB). The difference in arm circumference between preoperative and postoperative time points was checked in both groups.
Results: The mean number of identified blue stained arm nodes was 1.41±0.66. The mean follow up period was 16.24(3∼24)months. In the majority of patients (86.2%), arm nodes were located between the lower level of the axillary vein and just below the second intercostobrachial nerve. The location of the arm node was the inferolateral side of axillary and thoracodorsal vessels in 62 patients (53.4%), the inferomedial side in 46 patients (39.7%), the superolateral side in 5 patients (4.3%), and the superomedial side in 3 patients (2.6%) In the arm node unpreserved group, 5 patients (4.3%) had metastasis in their arm node. When comparing between arm circumferences in ipsilateral upper-extremity of the arm node preserved group and unpreserved group, in the SLNB group, there was no significant difference. But in the ALND group, the arm circumference changes of the arm node unpreserved group were bigger than that of the preserved group (0.50±1.15 vs 0.16±0.76, p = 0.066).

There were no lymphedema cases among the arm node preserved group, but one lymphedema developed in the unpreserved group(5.2%). There was no locoregional recurrence in both group in follow up periods.
Conclusion: After further follow-up, this study showed some differences in arm circumference between two groups. Arm node preserving was possible in all breast cancer patients with identifiable arm nodes, during ALND or SLNB, except for those with high surgical N stage, and lymphedema and locoregional recurrences did not develop in patients with arm node preserving surgery.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-05.
Abstract P1-01-08: A Nomogram for predicting two or less axillary lymph node involvement for breast cancer
Authors: Ahn SK , Kim JS , Kim Mk , Lee JW , Kim T , Kim JY , Moon HG , Han W , Noh D-Y 
Published: August 2014

Abstract
BACKGROUND: Completion axillary lymph node dissection (ALND) is currently the standard of care in the event of a positive sentinel lymph node biopsy (SLNB). However, result from Z0011 indicate that women with a one or two involved axillary nodes and clinical T1-T2 tumors undergoing lumpectomy with radiation therapy followed by systemic therapy do not benefit from completion of ALND in terms of survival. As a result, the use of intraoperative frozen section during SLNB will be declined.
OBJECTIVE: To define possible predictors of having two or less involved axillary node using preoperative image study to provide information for surgeons making decision about sparing intraoperative frozen section analysis of sentinel lymph node.
METHODS: We reviewed the records of 1214 patients with clinical T1-T2 and clinical node negative invasive breast cancer. None of these patients were in situ cancer on initial gun biopsy nor received neoadjuvant chemotherapy. Factors associated with having three or more involved axillary nodes were evaluated by univariate and multivariate logistic regression analysis.
RESULTS: Among 1214 patients, 203 patients (16.7%) had three or more positive nodes. On a multivariate analysis, having three or more positive nodes was associated with primary tumor size by breast US, axillary LN grade according to cortical thickness by US and presence of axillary LN enlargement on chest CT. The area under ROC curve corresponding to the multivariate logistic regression model applied to dataset of 1214 patients was 0.827 (95% CI: 0.793–0.860). When applied to a validation dataset of 378 patients, it was 0.899 (95% CI: 0.841–0.957). A nomogram to predict the probability of having two or less axillary nodes involvement based on patients' age and preoperative image findings was developed from the multivariate logistic regression model.
CONCLUSION: Patients with a low probability of having three or more positive nodes can be identified from preoperative image finding. The nomogram developed will be helpful to surgeons making decision about sparing intraoperative frozen section analysis of sentinel lymph.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-08.
Abstract P1-01-15: Accuracy of sentinel lymph node in determining the requirement for second axillary surgeries in early breast cancer with retrospective application of the Z0011 criteria.
Authors: Waters PS , Fennessy PJ , Alazawi D , Sweeney KJ , Kerin MJ 
Published: August 2014

Abstract
Background: Lymph node status is the most important prognostic marker in breast cancer management. The ACOSOG Z0011 trial reported no difference in survival in patients undergoing sentinel lymph node biopsy(SLNB) alone versus axillary lymph node dissection(ALND) in T1-T2 tumours with 1–2 positive lymph nodes.
Aims: Whether sentinel lymph node biopsy was a true representative of axillary burden. We also addressed whether application of criteria from Z0011 trial would have prevented patients undergoing second axillary surgery.
Methods: All patients with T1-T2 tumours undergoing sentinel node biopsy were included in our study (n = 1019). Analysis of our prospectively updated breast cancer database was performed. Minitab version 16.0 was used for statistical analysis.
Results: 1019 SLNB procedures for T1 & T2 tumours were performed over a 7 year period. 730 patients were reported as histologically negative and 289 were positive(&lt;1 node = 194, &gt;1 node = 95). Of the lymph node positive group, 223 patients progressed to axillary clearance. Staging of 149 patients remained unchanged with 74 patients being upstaged with having &gt;2 lymph nodes reported as positive. 72 patients from the SLNB negative group also had an axillary clearance. 5 of these patients had further axillary disease with 1 patient being upstaged having &gt;2 positive lymph nodes. With application of Z0011 criteria 220 patients would have avoided second axillary surgery.
Conclusions: The accuracy of sentinel lymph node biopsy in determining tumour burden has been demonstrated. Furthermore application of Z0011 will have major cost savings for the health service with decreased patient stay and morbidity.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-15.
Abstract P1-01-17: The impact of triple negativity on lymph node positivity in breast cancer.
Authors: Weber JJ , Bellin LS , Milbourn DE , Wong J 
Published: August 2014

Abstract
Introduction: Triple negative breast cancer (TNBC), defined as estrogen, progesterone, and HER2/Neu receptor-negative is biologically more aggressive than non-TNBC. Whether TNBC presents at a more advanced local/regional stage is controversial. We sought to determine whether TNBC had more frequent lymph node positivity.
Methods: ER and PR status was determined by routine immunohistochemical analysis. HER2/Neu status was determined by immunohistochemistry; if 2+ equivocal status was noted, fluorescence in situ hybridization was performed for confirmation. Patients with a clinically negative axilla underwent sentinel lymph node biopsy, and if the sentinel node was positive, underwent immediate completion axillary node dissection. Lymph node positivity was determined by hematoxlyn-eosin staining. The main outcome measures were lymph node status and pathologic tumor size. Statistical differences were compared by means of paired t-test and chi-squared test where appropriate.
Results: Between January 1, 2004 and December 31, 2010, 501 women with invasive breast cancer were treated at our institution. These patients ranged in age from 25 to 93 years (mean 57.6 yr), with 53.1% of patients self-reported as non-Hispanic white and 43.7% non-Hispanic black. TNBC patients were younger (mean 55.0 yr vs. 58.3 yr, p = 0.005), and were more often non-Hispanic black (52.7% vs. 41.1%, p = 0.03). The mean pathological tumor size of the entire population was 1.86 cm (range 0 to 18 cm). One hundred twelve patients (22.4%) were TNBC. The mean pathological tumor size for TNBC compared to non-TNBC patients was 2.07 cm (range 0 to 8.7 cm) and 1.80 cm (range 0 to 18 cm) (p = 0.068). There was a statistically significant difference in the T-stage at presentation between TNBC and non-TNBC tumors (T1, 58.9% TNBC vs. 72.0% non-TNBC; T2, 34.8% TNBC vs. 22.4% non-TNBC; T3/T4, 6.3% TNBC vs. 5.6% non-TNBC, p = 0.02). One hundred sixty patients (31.9%) were node positive. The number of positive lymph nodes in the TNBC patients ranged from 1–18, and the non-TNBC ranged from 1–35 (TNBC mean 2.94 vs. non-TNBC mean 3.94, p = 0.09). TNBC patients were more often node positive than non-TNBC (39.3% vs. 29.3%, p &lt; 0.05). However, when stratified by T-stage, the differences did not achieve statistical significance (T1, 31.8% TNBC vs. 21.8% non-TNBC, p = 0.11; T2, 51.3% vs. 46.0%, p = 0.70; T3/T4, 57.1% vs. 59.1%, p = 1.0), despite a trend toward greater node positivity in earlier T-stage TNBC tumors.
Conclusions: TNBC is more frequently lymph node positive than non-TNBC. This is largely attributable to more node positivity in early T-stage tumors. These data provide further evidence for the poor prognosis of TNBC and the increased likelihood of nodal metastases in early T-stage tumors.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-17.
Abstract P1-01-18: The results of 55 consecutive cases of intra-operative sentinel node analysis using real time polymerase chain reaction detection of cytokeratin 19 and mammoglobin expression (Metasin) to direct immediate axillary clearance.
Authors: Nadi K , Sharaiha Y , Sai-Girdhar P , Huws A , Khawaja S , Holt S 
Published: August 2014

Abstract
The standard management of early beast cancer is complete excision of the primary from the breast by either wide local excision or mastectomy and sentinel node biopsy to stage the axilla. The standard of care in the UK remains clearance of the axilla in node positive patients. Unless immediate multiple frozen section histology is available, positive patients require a second operation between 3 and 6 weeks later, with the associated increased cost, inconvenience and risk.
By using the real time polymerase chain reaction (PCR) to detect mammary derived cells in the sentinel lymph nodes (SLN), we aim to provide the surgeon with a reliable indicator of the presence or absence of nodal macro-metastases within a timeframe that will allow axillary clearance to be performed under the same anaesthetic as the initial surgery. We detect cytokeratin 19 (CK19) or mammoglobin within the lymph node using reagents developed by the UK National Health Service under the name Metasin.
Method: 55 consecutive patients undergoing SLN biopsy as part of their initial treatment for early breast cancer were tested using the Metasin. The nodes were divided into 2mm slices and alternate sections submitted to PCR and the remainder to conventional histology. The results were compared and an assessment of the costs made. The time taken report the Metasin result to the surgeon was recorded.
Results: Five patients had positive results by Metasin and proceeded to immediate axillary clearance. When compared to histology there were no false positive results (0%). Two patients were negative on Metasin testing with the threshold set at 2 mm but positive on histology (3.6%). The average time for the test was 43.2 minutes and the mean number of lymph nodes was 2.3. The average cost is £40 to test 2 nodes.
Discussion: The test is accurate. The two false negative cases were found to be due to the sampling, the metastases being only present by chance in the histologically examined specimens and not due to assay failure. The total cost to run the test for 55 patients was £2,520. The cost for completion axillary clearance as a separate procedure is estimated at £2,227. The total saving for 5 cases is about £11,000, making the test cost saving as well as safer, more acceptable to the patients and limiting delay in starting adjuvant therapies. The additional time of surgery caused by using Metasin was minimal.
Conclusion: Metasin has become our standard of care in patients requiring SLN biopsy and generally avoids second surgeries to clear the axilla in positive cases. We are considering analyzing the complete node using this technique and this would eliminate false negatives caused by sampling and offer further cost savings in the histology department.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-18.
Abstract P1-01-25: Sentinel lymph node biopsy in breast cancer: The approach in day surgery under local anaesthesia for quality-of-life and significant cost reduction
Authors: Ricci F , Capuano LG , Saralli E , Di Legge P , Violante A , Polistena A , Scala T , Pacchiarotti A , Cannas P , Cianni R , Fanelli G , Bellardini P , De Masi C 
Published: August 2014

Abstract
Background: Sentinel lymph node biospy (SLNB) is widely used in the management of breast cancer patients without axillary metastases or inflammatory breast cancer (IBC).
Methods: From Jan. 1st 2006 through Dic. 31st 2011 we performed 302 SLNB at St. M. Goretti Hospital. Mammary carcinoma was diagnosed as malignant by aspiration citology and/or biospy. In all cases with positive citology or biospy, we performed quadrantectomy and SLNB at the same time. All patients underwent pre-operative lymphoscintigraphy with intradermal pericicatritial and/or periareola injection of 12–15 MBq 99Tc colloidal albumin particles 50–80 nm size range, in 0,2 ml saline solution. We never used vital blue dye. All patients underwent surgical treatment 3–12 h. later. We performed SLNB and quadrantectomy in day surgery (DS) and local anaesthesia (LA) with 2% of Carbocaine. Axillary incision was 3–4 cm. This study was approved by an ethics committee, was discussed with all patients and informed consent was obtained.
Purpose of the study is to investigate the approach in DS under LA for quality of life and significant cost reduction.
Results: Six patients underwent pre-operative lymphoscintigraphy the radiotracer did not show any sentinel lymph node (SLN), in five cases we performed axillary dissection (AD). In one case of young patient who had previously been treated with chemotherapy for non-Hodgkin's lymphoma, negative positron emission tomography (PET), we performed quadrantectomy without AD. In three cases the axilla was positive. In four cases of multifocal (MF) and two of multicentric (MC) invasive breast cancer, the SLN was identified in axilla and SLNB was perfomed. SLNB in MF and MC tumors was similar to unifocal cancers. Only one case of MC cancer the SLN was positive. Six patients classified T4b according to AJCC, were treated with neoadjuvant chemotherapy (NC). The axilla was negative to ultrasound (US), PET and citology. After completion of NC, lymphatic mapping was able to identify SLN and we performed SLNB. In these patients SLN was negative. In two cases of male cancer the axilla was negative to clinical examination, in both cases SLN was positive for macrometastases. Six cases showed axillary isolated tumor cells (ITC). Eighteen micrometastases. Thirty-two macrometastases. In two case of negative SLN there was a positive second palpable lymph node. One case showed a double SLN in the axilla and internal mammary chain, only the internal mammary lymph node was positive.
The SLN identification rate was 99%. After surgery we distributed a questionnaire to the patients about the acceptability of this approach.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-25.