bluuebunny/crossref_metadata_2025_split huggingface dataset:
P3-06-04: Sno/miRNA Expression Via Next Generation Sequencing: Variation in Patients before and after Treatment.
Authors: Banerjee N , Kamalakaran S , Varadan V , Janevski A , Lezon-Geyda K , Bossuyt V , Flowers D , Sikov W , Abu-Khalaf M , Rizack T , Harris L , Dimitrova N 
Published: June 2012

Abstract
Background
Aberrant expression of small RNA molecules has been shown in breast cancer. It is yet unclear if variation exists in small RNA molecule expression in response to treatment. Since next generation sequencing offers more globally sensitive detection of sno and miRNAs, we performed an RNA-seq study to explore patients pre- and post- brief exposure to treatment.
Methods: We sequenced transcriptomes of frozen biopsy samples from 8 breast cancer patients enrolled in a clinical trial for neoadjuvant therapy using trastuzumab (HER2 positive) or bevacizumab (HER2 negative) with chemotherapy. Tumor core biopsies were taken before and after 10 days of either biologic or nab-paclitaxel treatment and stored in OCT compound. Total RNA was extracted and libraries were constructed for the 16 samples using TruSeq (Illumina). We performed 74bp paired-end sequencing with the Illumina GAII platform. Sequences were aligned to the sno/miRNA track (containing 928 miRNAs and 413 snoRNAs) in UCSC and read counts were determined using Bowtie. We performed differential miRNA and snoRNA expression analysis pair-wise in all pre- and post-therapy samples. Given that miRNA deregulation relies on their protein-coding gene targets, we analyzed the predicted targets of the significantly varying miRNAs for functional enrichment.
Results: Each sample had on average 46 million paired-end reads, of which on average 70% were mapped to the human genome. Overall, we detected 138 miRNAs in at least one sample, with each sample expressing 33 miRNAs on average. We detected a total of 11 miRNAs (7%) that showed significant differential expression with treatment. Interestingly, 6 of these miRNAs varied in all patients. The predicted targets of these miRNAs were enriched in DNA-dependent transcription, gene expression, cell proliferation and cell communication. Similarly, we detected 202 snoRNAs in at least one sample, with each sample expressing 87 snoRNAs on average. Of these, we found 21 snoRNAs (10%) to vary significantly upon treatment and 6 of these snoRNAs showed expression changes in all patients.
Conclusions: These results suggest that variation in sno/miRNA expression may play a role in response to treatment. The consistent variation of sno/miRNAs in response to treatment suggests shared small RNA-mediated mechanisms. If validated, these results suggest that next generation sequencing technologies will allow lead to improved methods of stratifying, subclassifying and managing breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-06-04.
P3-07-05: Nomogram Incorporating SLN Metastasis Size Provides the Most Accurate Prediction of Non-SLN Involvement in Breast Cancer Patients.
Authors: Gainer SM , Mittendorf EA , Hunt KK , Bassett RL , Yi M , Meric-Bernstam F , Ross MI , Babiera GV , Kuerer HM , Caudle AS , Hwang RF 
Published: June 2012

Abstract
Introduction: The finding of metastatic disease in the axillary nodes remains an important factor that guides adjuvant therapy decisions in breast cancer. The value of completion axillary lymph node dissection (ALND) may not be the same in all patients and determining the risk of non-SLN involvement can be a guide in surgical decision making. We recently developed a nomogram that incorporates the maximum SLN metastasis size to predict non-SLN axillary involvement (Mittendorf et al., Ann Surgery 2011,in press). The purpose of this study was to compare the accuracy of this nomogram to another widely used nomogram that does not include SLN metastasis size.
Methods: We queried a prospective breast cancer database for patients with clinically negative nodes undergoing sentinel node biopsy who did not receive neoadjuvant therapy. We identified 431 patients with invasive breast cancer treated from 1996 to 2007 who had a positive SLN and underwent completion ALND. We evaluated clinicopathologic data including histology, multifocality, nuclear grade, pathologic tumor size, number of SLNs recovered, number of positive SLNs, maximum SLN metastasis size, presence of extranodal extension, hormone receptor status, and presence of lymphovascular invasion. Data were entered into our nomogram and the nomogram that does not include SLN metastasis size. The accuracy of the 2 nomograms in predicting non-SLN axillary metastasis was compared in all patients and in subgroups of patients based on burden of disease in the SLN.
Results: For the entire cohort of 431 women with positive SLNs, our SLN size nomogram was more accurate in the detection of non-SLN disease (area under the receiver operating characteristic curve [AUC] 78.3% vs. 72.4%, p=0.01). Whether or not SLNs were subjected to frozen section did not influence the relative accuracies of the 2 nomograms. When patients were analyzed by burden of disease in the SLNs, our SLN size nomogram was more accurate in predicting non-SLN disease in patients with macrometastases in the SLN (AUC 77.3% vs. 70.3%, p=0.008). There was no significant difference in the accuracy of the 2 nomograms for patients with isolated tumor cells or micrometastases in the SLNs.
Conclusions: Our nomogram incorporating SLN metastasis size with other clinicopathologic factors is the most accurate predictor of the risk of non-SLN metastasis in patients with a positive SLN. The SLN size nomogram is highly accurate in women with macrometastases, who may benefit the most from completion ALND. Using a nomogram with SLN metastasis size can provide the most accurate information for patient counseling and surgical decision making.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-05.
P3-07-06: Prognostic Utility of Upfront Nodal Staging Prior to Neoadjuvant Chemotherapy: The UAB Experience.
Authors: Keene KS , De Los Santos JF , Krontiras H , Hinton B , Meredith R , Li Y , Carpenter JT , Bland K , Forero A 
Published: June 2012

Abstract
Purpose: Controversy exists regarding the prognostic utility of upfront lymph node staging in patients receiving neoadjuvant chemotherapy. This retrospective study explores whether upfront verses outback nodal staging influenced locoregional control and survival endpoints. Methods: Between 1999 and 2005 one hundred and fifteen patients treated with neoadjuvant chemotherapy at UAB were identified. Patient, tumor, and treatment variables were recorded. Timing of nodal assessment was based on either surgeon preference or stipulated upfront per several clinical protocols. Survival was measured using the Kaplan Meier statistics. Univariate and multivariate analyses of covariates associated with local-regional control (LRC), progressionfree (PFS) and overall survival (OS) were performed. Results: Mean age was 49 years and mean follow-up was 5.8 years. Stage distribution was as follows: 40 IIA, 34 IIB, 26 IIIA, 10 IIIB, and 5 IIIC. Definitive surgery included breast conservation in 49 patients, total mastectomy in 21 and modified radical mastectomy in 44. Seventy-two patients had upfront nodal sampling before neoadjuvant therapy, 36 by fine needle assessment and the remainder by sentinel node biopsy. Forty-three patients had their nodal assessment following neoadjuvant chemotherapy. Of those with upfront nodal staging: forty nine patients had a positive nodal result and 23 had negative findings. In those that were sampled at the time of definitive surgery: 21 had positive results, 21 had a negative result, and 1 patient did not have any nodes in the specimen. One hundred five patients had post-operative radiation therapy. Overall there was no difference in LRC, PFS or OS outcomes between patients that had an upfront nodal staging procedure and those that had their nodes sampled at the time of definitive surgery. Patients achieving pCR had a non-significant trend towards improved overall survival (p=0.12). Final pathologic T, N and group stage were statistically significant in determining the progression free, p=0.003, 0.011, 0.005 and overall survival, p=0.02, 0.037, and 0.009. Lymphovascular space invasion was associated with progression free survival on univariate analysis, p=0.0179, but not multivariate analysis. Other covariates including age, biologic subtype, grade, type of chemotherapy, use of radiation therapy, radiation volume, time to complete radiation therapy, and use of hormonal therapy did not affect outcomes. Discussion: Upfront as compared with outback lymph node staging did not influence locoregional control or survival endpoints. Final pathologic stage and not initial clinical stage remains the most important prognostic factor associated with survival.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-06.
P3-07-12: Value of Preoperative Ultrasound-Guided Axillary Lymph Node Biopsy for Preventing Futile Sentinel Node Procedures in Breast Cancer: A Systematic Review and Meta-Analysis.
Authors: Diepstraten SC , Sever AR , Buckens CF , Veldhuis WB , van den Bosch MA , Mali WP , Verkooijen HM 
Published: June 2012

Abstract
Purpose: Women affected with invasive breast cancer generally undergo sentinel node biopsy (SNB) of the axilla, which is followed by axillary dissection if lymph node metastases are found. This systematic review and meta-analysis aims to evaluate the utility of preoperative axillary ultrasound-guided needle biopsy in terms of staging the axilla and preventing futile SNB.
Methods: We systemically searched Pubmed, Embase and Cochrane through March 14, 2011, for studies addressing preoperative assessment of axillary lymph node (ALN) status by axillary ultrasound and biopsy. Eligible studies had to report on biopsy indication and method, and true and false positive and negative outcomes. A pooled estimate was calculated for prevalence of futile SNB (defined as the proportion of patients needing secondary ALN dissection after a negative axillary ultrasound and biopsy) and sensitivity (defined as the proportion of patients with ALN involvement detected by axillary ultrasound and biopsy).
Results: Twenty-three studies were included which reported on a total of 6205 procedures. The pooled prevalence of futile SNB was 25% (95% CI = 23% to 27%) and the pooled sensitivity was 51% (95% CI = 43% to 59%). There was substantial heterogeneity across studies for both futile SNB prevalence (I2 = 60.5) and sensitivity (I2 = 93.3), which could not be explained by between-study differences in biopsy technique, inclusion criteria, biopsy indication or study design. Sensitivity was increased in studies with a high prevalence of axillary lymph node metastases.
Conclusion: Preoperative axillary ultrasound guided biopsy is a useful step in the process of axillary staging as around fifty percent of breast cancer patients with axillary involvement can be identified pre-operatively and are spared a two step surgical intervention. Still, one in four women with a US biopsy ‘proven’ negative axilla have ALN involvement on SNB and need to undergo completion axillary dissection. New techniques may be able to reduce the prevalence of futile SNB.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-12.
P3-07-17: Optimal Number of Sentinel Lymph Nodes That Could Avoid Completion of Axillary Lymph Node Dissection in Operable Breast Cancer.
Authors: Salmon RJ , de Ricke Y , Falcou MC 
Published: June 2012

Abstract
Background
Axillary lymph node dissection (ALND) has been the standard of care for breast cancer patients with sentinel lymph node (SLN) metastasis. It is now under discussion since the publications of ACOZOG Z0011 and NSABP-32. The 1–3% rate of axillary recurrence is very low in these studies, whereas the rate of additional nodal metastasis after the completion of ALND varies from 15% to 35%. The purpose of this study was to determine the optimal number of nodes to be removed in order to obtain an axilla free of disease after initial surgery.
Patients and methods: 4928 consecutive patients treated for breast cancer ≤ 2 cm with primary breast surgery with SNB between 2000 and 2009 were reviewed from the Institut Curie breast cancer prospective database. 1165 patients with a positive SLN (macrometastasis, micrometastasis and isolated tumor cells) underwent ALND. The proportion of patients with positive ALND was analysed according to the total number of sentinel lymph nodes biopsied. Results were compared with Chi-square test for qualitative variables and with Kruskal-Wallis for quantitative variables.
Results: Among the 1165 patients, 308 (26.4%) had a positive ALND. Among them, 81.1% of patients had a macrometastasis in the SLN versus 45.6% in the 857 patients with negative ALND (p&lt;0.0001); 10.8% had a micrometastasis versus 31.4% (p&lt;0.001) and 8.1% of patients had isolated tumor cells in the SLN versus 23% (p&lt;0.001). The proportion of patients with positive ALND decreased with the number of sentinel nodes removed (Figure 1), independently of the number of positive SLN. Among the 1165 patients, the rate of patients with 5 nodes removed or more and with residual disease in the axilla was &lt; 1% (n=11). Those patients could have avoided completion ALND, representing 3.6% of the total positive ALND that would have been neglected.
Conclusions: We showed that patients with positive SLN have a very low risk (&lt;1%) of residual disease in the axilla when 5 nodes or more have been removed. This number which is a major component of nomograms, could be used as a threshold to avoid completion ALND.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-17.
P3-07-21: Sentinel Lymph Node Metastasis Are More Likely To Develop in Triple Positive Breast Cancer Patients without Compromising Disease Free Survival.
Authors: Rubio IT , Espinosa-Bravo M , Cebrecos I , Sao A , Peg V , Di Cosimo S , Cortes J , Xercavins J 
Published: June 2012

Abstract
Background. Lymph node metastasis are the most significant prognostic factor for breast cancer (BC) patients and the use of sentinel lymph node biopsy (SLN) has generated an increased detection of positive nodes. In the last years, molecular subtypes have provided additional information on local recurrence and survival in BC patients. The objective of this study is to evaluate the correlation between axillary SLN metastasis and molecular subtypes and whether this may have prognostic implications.
Methods. A total of 497 patients with clinically node negative T1-T3 breast cancer underwent SLN biopsy from 2005 to 2009. Patients were divided in two groups depending on the timing of SLN biopsy. Patients were classified according to ER/PR/Her2 status as (ER/PR/HER2 + (TP), ER/PR/HER2 - (TN), ER/PR/+ HER2 - and ER/PR -HER2 +). For SLN metastasis the following variables were tested in univariable and multivariate models: age, tumor grade, tumor type, and the combined hormone receptors and HER2.
Results: The SLN was positive in the surgery first group in 127 of 429 patients (29.6 %) while in 27 patients (34.7%) in the neoadjuvant group (p = 0.08). Forty patients (8.1%) were classified as TP, 25 (5.1%) as ER/PR - HER2 +, 364 (73.2%) as ER/PR+ HER2 - and 68 (13.6%) as TN. Triple positive BC patients were more likely to have axillary SLN metastasis compared to other molecular subtypes (p &lt; 0.006). Multivariate logistic regression revealed age (≤ 50 years) and TP tumors to be independent predictors of SLN metastasis. Odds ratio (OR) for TP vs other molecular subtypes was 3.646 (IC 95% 1.566−8.488). OR for age ≤ 50 years was 2.353 (IC 95% 1.554−3.559). Disease free survival in TP patients tended to be longer compared to ER/PR - Her2 + and TN patients.
Conclusions. Her 2 overexpression favours SLN metastasis in ER/PR positive tumors over other ER/PR status. Even with increased SLN metastasis, TP breast cancer patients do better than TN and ER/PR -/Her2 positive patients. Molecular subtype classification may holds more potential value in the decision-making process in patients with BC than the currently staging system.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-21.
P3-07-24: Accuracy and Cost Effectiveness of Frozen Section Examination of the Sentinel Lymph Node (SLN) in Ductal Carcinoma In Situ (DCIS) of Breast.
Authors: Ballehaninna UK , Santoro E , Schaefer SS , Blackwood MM , Chamberlain RS 
Published: June 2012

Abstract
Background: SLN biopsy (SLNB) can avoid reoperation for axillary staging in DCIS patients upstaged to invasive breast cancer (IBC) following resection. Intraoperative frozen section (IFS) examination of the SLN is a widely accepted tool for IBC patients in order to select candidates for axillary lymph node dissection (ALND), and avoid reoperation. Until now, utility of IFS in DCIS patients has not been addressed.
Methods: Data from DCIS patients undergoing resection with SLNB (2000-11) was analyzed to determine the utility and cost of IFS exam and its impact on axillary management. A binomial regression analysis was performed to assess factors predictive of IFS positivity and SLN metastases (SLNM).
Results: 401 patients (core biopsy, N=276, or excisional biopsy, N=125) underwent partial (N=84) or total mastectomy (N=317) with SLNB. 77 patients (19.2%) were upstaged to IBC. SLNM were identified in 24 patients (5.9%). Immunohistochemistry (IHC) positive individual tumor cells (ITCs) was the most common pattern of SLNM (N=12, 50%), SLN micrometastasis (SLNmi) was identified in 9 patients (37.5%) and macrometastases in 3 patients (12.5%). IFS exam was positive in only 5 patients (1.2%) with a sensitivity and specificity of 20.8% and 100%. IFS was negative in 396 patients (98.7%) yielding a false negative rate (FNR) of 79.2%.

IFS costs $300,480 in DCIS patients of which only $2,970 was applicable to IFS positive patients (N=5). 11 of 24 patients with SLNM underwent ALND, revealing only 1 patient with further metastasis. Presence of IBC or DCIS with micro-invasion, multi-focal/multi-centricity, and advanced tumor stage were associated with SLNM (p&lt;0.05), however no clinico-pathologic variables were predictive of IFS positivity.

Conclusions: Most common patterns of SLNM in DCIS (ITCs/SLNmi) were identified only on routine pathologic assessment. Utility of IFS examination in DCIS patients is limited by poor sensitivity, high FNR and increased costs. Higher axillary nodal metastases are rare and prognostic significance of SLNmi/ITCs in DCIS is unproven. IFS examination of SLN in DCIS can be safely omitted and ALND should be performed only for SLN macrometastases.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-24.
P3-07-28: One Step Nucleic Acid Amplification (OSNA) for Intraoperative Molecular Detection of Lymph Node Metastases and Micro-Metastases in Breast Cancer.
Authors: Babar MM , Madani R , Jackson P , Irvine T , Layer G , Kissin M 
Published: June 2012

Abstract
Introduction: Ideally, intraoperative sentinel lymph node analysis in breast cancer should be automated, concordant with histopathology and practically applicable. One step nucleic acid amplification (OSNA), a highly sensitive intraoperative assay of cytokeratin 19 mRNA, is used for the detection of sentinel lymph node (SLN) macro- and micro-metastases in breast cancer. Guildford adopted the intraoperative OSNA “live” in December 2008 after undertaking a multicentre evaluation of its accuracy and high concordance with histopathology and here we present our two year data since its introduction.
Methods: Data was collected prospectively from 2008–10. All patients eligible for sentinel node biopsy were offered OSNA and operations were performed by five consultant breast surgeons. On detection of micro-metastasis (+) and positive but inhibited metastases a level 1 axillary nodal clearance (ANC) and for a macro-metastasis (++), a level 3 ANC was performed.
Results: 471 patients had 999 SLN analysed, median age being 61. All except one were females. 72% (n=340) had wide local excision, 26% (n=120) underwent mastectomy and 2% (8) SNB alone. Mean tumour size was 18.3 mms. 80% (n=371) of the cases were IDC and 55% (n=256) had grade II tumour. 34% (n=161/471) had positive SLN who had further ANC. Of these, 48% (n=78/161) had macro-metastases, 37% (n=59/161) had micro-metastases and 15% (n=24/161) had positive but inhibited results. 17% (10/59) of the patients with micrometastases had positive non-SLN (NSLN), four (4/59, 6.8%) had four positive nodes (SLN+NSLN) thus receiving adjuvant radiotherapy. 8% (2/24) of those with positive but inhibited results and 39% (30/78) of those with macro-metastases had positive NSLN.
Conclusion: Over a third of patients had OSNA positive SLN and underwent axillary surgery at the same operation. This technique eliminates the need for a second operation in sentinel lymph node positive patients and avoids the anxious wait for results in all, streamlining the patient's cancer journey. OSNA upstages patients with micro-metastases and long term studies are needed to determine the clinical relevance of molecular micro-metastatic disease.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-28.
P3-10-01: Alternative Dosing Regimens with the EGFr Inhibitors (Gefitinib and Lapatinib) in Mammary Cancer Models: Prevention and Therapeutic Efficacy.
Authors: Lubet RA , Bode AM , Szabo E , Grubbs CJ 
Published: June 2012

Abstract
The EGFR inhibitors are effective in treatment of lung and pancreatic cancers (erlotinib, gefitinib) and Neu overexpressing breast cancer (lapatinib) in humans; as well as preventing multiple cancers in animal models. However, the development of toxicities (Iressa, skin rashes; Lapatinib, diarrhea) limit their potential use in prevention; and perhaps even in an adjuvant setting. We examined whether alternative dosing regimens which might reduce toxicity would still achieve preventive and therapeutic efficacy. Female Sprague-Dawley rats were administered a single IV dose of methylnitrosourea (MNU) at 50 days of age. In a prevention study, MNU treated rats administered Gefitinib daily (10 mg/kg BW/day, 7x/week) or Gefitinib (70 mg/kg BW, 1x/week) beginning 5 days after MNU resulted in 94 and 75% reductions, respectively, in cancer multiplicity. Simultaneous measurements of tumor load (number of tumors x tumor weight) showed that both regimens resulted in greater than a 90% decrease. In the therapeutic study (initiating treatment when animals developed a small palpable cancer), both regimens were again highly effective. A prevention study was also performed with Lapatinib (75 mg/kg BW/day, 7x/week or 525 mg/kg BW, 1x/week). While the daily dose reduced cancer multiplicity 90%, the weekly dose caused a 70% reduction. Finally, we examined the effects of daily or weekly dosing with Iressa (100 mg/kg BW/day, 5x/week or 500 or 250 mg/kg BW, 1x/week) in an ER− mouse model (using MMTV-Neu; p53+/− mice). This study showed that while daily dosing with Iressa decreased tumor multiplicity roughly 80%, weekly dosing at either dose caused roughly a 50% decrease. These data show that even a significant alteration in the dosing of Gefitinib (EGFR 1) or Lapatinib (EGFR 2/1) still resulted in a large reduction in mammary cancers. The important clinical question will be whether this altered dosing will diminish the toxicities associated with these agents. We cannot determine this in animal models since, at the effective doses employed, the typical toxicities observed in humans are not observed. Supported by NCI contract number HHSN261200433001C.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-10-01.