bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract ES3-1: Evaluation of Breast Cancer Predisposition in Different Clinical Venues
Authors: Plon SEE
Published: April 2011

DNA sequence-based cancer susceptibility testing of the BRCA1/2 genes is now one of the most commonly ordered genetic tests in the United States. Increasingly sophisticated computer models help to inform the clinician as to the probability of identify a cancer-associated mutation based on both the nature of the tumor, e.g. estrogen receptor status, the age of onset of cancer, presence of ovarian cancer and the family history of the patient. However, even in clearly high-risk families there are additional levels of complexity which impact the cost of the testing, test choice and the usefulness of the results. Whenever possible it is preferable to initiate testing with an individual with cancer first, in order to clarify whether a BRCA1/2 mutation is responsible for the cancer susceptibility. Results of comprehensive sequence analysis can include either negative, deleterious mutation or variant of uncertain significance (VUS). Currently, the potential cancer risk associated with a VUS result is very broad which leads to confusion among providers and patients. Recommendations for further classifying these VUS results into risk stratified categories to aid clinical decision making have been proposed and efforts to implement these recommendations are being initiated by international groups. A key reason to pursue genetic testing is to identify which healthy relatives are at increased of cancer. Thus, to maximize the cost effectiveness of genetic testing, research on how testing is being performed on these downstream relatives is needed. In particular, the most efficient and least expensive testing requires that physicians caring for the relatives have available the detailed test results of the cancer patient. If the cancer patient carries a VUS, then testing of the healthy relative is typically not indicated. If the cancer patient carries a deleterious mutation, then testing of the relative should be for that specific mutation known as single site testing (or familial mutation testing). Our group queried physicians across five different medical specialties (family medicine, internal medicine, obstetrics/gynecology, general surgery and hematology/oncology) for test recommendations of at-risk relatives. The majority of physicians recommended full BRCA1/2 sequencing of a healthy at-risk relative whether provided information that the relative with cancer carried a deleterious mutation or VUS. These findings were not impacted by the physician's own experience with BRCA1/2 testing and potentially result in tenfold higher testing costs compared with national recommendations. Thus, utilization of genetic professionals and improved education of diverse physician specialties about family-centered genetic test decision making may improve efficacy of risk prediction and substantially reduce costs associated with genetic testing for cancer susceptibility.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr ES3-1.
Abstract ES3-2: Challenges to Clinical Application of New Discoveries in the Genetics of Breast Cancer Predisposition
Authors: Robson ME
Published: April 2011

In the United States, testing for mutations in BRCA1 and BRCA2 has become a routine part of the management of individuals at risk for hereditary breast and ovarian cancer. Most providers accept the clinical utility of such testing. This acceptance rests upon a consensus that clinical management of mutation carriers should differ from that of non-carriers. The factors that justify differential management are: 1) the strength of the predisposition, 2) the strong association between mutation and risk in an individual, which allows presymptomatic testing, 3) the risks for component tumors that may not be evident from the family history, and 4) the availability of interventions that are perceived to be effective, even if the evidence base demonstrating such effectiveness is less than robust. Evolving evidence that affected mutation carriers may benefit from specific local or systemic treatment approaches further increases acceptance. Only a small number of breast cancer patients carry BRCA1 and BRCA2 mutations. A few more women carry other high penetrance alleles, but the clinical utility of testing for some of these (e.g. TP53) is less clear than for BRCA1/2, which illustrates that the strength of a predisposition is not the only determinant of clinical utility. High penetrance alleles only account for a small fraction of the hereditable risk of breast cancer. Several groups have described a number of rare variants of lesser risk (RR approximately 2), such as ATM, CHEK2, BRIP1, and PALB2). Large genome-wide association studies have identified additional common variants with even lower relative risks. The identification of these rare and common risk variants may provide important insights into breast cancer biology, but the clinical utility of testing is limited at the present time. We will discuss possible approaches to incorporating information about these risk variants into clinical practice.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr ES3-2.
Abstract ES6-2: Cell to Cell Variability in the Responses of Tumor Cells to Death Ligands and Other Anti-Cancer Drugs
Authors: Sorger PK , Spencer S , Gaudet S , Aldridge B , D Flusberg
Published: April 2011

Cell to cell variability in phenotype and fate is important for tissue homeostasis, the emergence of drug resistance and the evolution of tumors. I will discuss cell to cell variability in the responses of clonal populations of human cells to TRAIL, a prototypical inducer of receptor-mediated (extrinsic) apoptosis and an investigational therapeutic, as well as to other pro-apoptotic drugs. Some TRAIL-treated human cells die within ∼40 min, others only after 12 hr and some live indefinitely. During this variable delay initiator caspases (ICs) are active in processing substrates such as Bid and downstream effector caspases (ECs) but mitochondrial membrane permeablization (MOMP) does not occur and (ECs are catalytically inactive. We have explored three explanations for cell to cell differences among members of a clonal and notionally uniform population: (i) genetic or epigenetic variation (ii) the involvement of one or more biochemical processes subject to stochastic fluctuation (iii) difference in cell state such as position in the cell cycle or protein concentrations. To distinguish these three possibilities we compared the fates of sister cells exposed to TRAIL and other drugs using live-cell microscopy. Genetic and epigenetic factors are transmitted with near-perfect fidelity; reaction rates dominated by stochastic fluctuations are no more similar in sisters than in any two cells chosen at random and variability arising from differences in mRNA or protein levels should be transiently heritable (because division is a binomial process in which sister cells inherit roughly equal numbers of abundant cytosolic and nuclear factors but drift towards the population average over time). The later explanation is correct — natural fluctuations in protein levels dominate phenotypic heterogeneity in extrinsic apoptosis and cause transient phenotypic heritablility. Variability can be manipulated by protein over-expression and drugs and I will describe analytic methods for modeling these perturbations mathematically. A key conclusion from this work is that variability in the responses of cells to drugs is inherent to the stochastic operation of the biochemical pathways that anti-cancer drugs target. Fractional killing is one inevitable consequence.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr ES6-2.
Abstract ES9-1: Long-Term Management of Pain Due to, and after, Primary Treatment of Breast Cancer
Authors: Rabow MW
Published: April 2011

As more women are living longer after treatment for breast cancer, survivorship issues take on even greater importance. As a result of effective breast cancer treatment, approximately one-half of survivors experience chronic pain due to the lasting sequelae of surgery, radiation, chemotherapy, and/or endocrine treatment. Research also suggests that these pain symptoms are under-reported and under-treated. The sources of chronic pain after breast cancer surgical treatment include nerve injury, scarring, lymphedema, and post-breast cancer treatment syndrome. After radiation, scarring, neuropathy, and lymphedema are possible. Multiple cytotoxic chemotherapy agents, including Paclitaxel, can cause a chronic painful peripheral neuropathy. Endocrine treatments, including Aromatase Inhibitors and bisphosphonates, are associated with bone, muscle and joint pain.

Treatment for these pain syndromes should be guided by basic principles of analgesia and directed by an understanding of the type of pain involved (nociceptive or neuropathic). Evidence-based treatment modalities include pharmacologic agents, including NSAIDS, acetaminophen, opioids and co-analgesics including neuropathic agents and antispasm medications. Non-pharmacologic treatments include exercise, physical therapy, heat, and cold. Integrative practices may be effective as well, including acupuncture, guided imagery, and massage. Diet and weight loss also have a role. Finally, emotional support for patients facing chronic pain, as will as the attendant concerns about the meaning of that pain, is key in helping ameliorate the distressing experience and disability of chronic pain. Support groups, cognitive behavioral therapy, and psychodynamic therapy all may be helpful to the survivor facing chronic pain after breast cancer treatment.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr ES9-1.
Abstract MS1-1: Noncoding RNA — The New Frontier in Breast Cancer Patients Management
Authors: Calin GA
Published: April 2011

MicroRNA and other short or long non-codingRNAs alterations are involved in the initiation, progression and metastases of human breast cancer. The main molecular alterations are represented by variations in gene expression, usually mild and with consequences for a vast number of target protein coding genes. The causes of the widespread differential expression of non-codingRNAs in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the processing machinery. MicroRNA and other short or long non-codingRNAs expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify non-codingRNAs that may represent downstream targets of activated oncogenic pathways or that are targeting protein coding genes involved in breast cancer. Recent studies proved that miRNAs and non-coding ultraconserved genes are main candidates for the elusive class of cancer predisposing genes and that other types of non-codingRNAs participate in the genetic puzzle giving rise to the breast malignant phenotype. These discoveries could be exploited for the development of useful markers for diagnosis and prognosis, as well as for the development of new RNA-based cancer therapies.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr MS1-1.
Abstract MS2-1: Trends in the Local Treatment of Breast Cancer
Authors: Tuttle TM
Published: April 2011

The objective of this presentation is to evaluate recent patterns in the local treatment of breast cancer in the United States. We will concentrate on 3 specific trends: 1) mastectomy/breast-conserving surgery (BCS) rates; 2) contralateral prophylactic mastectomy (CPM) rates; and 3) use of radiation therapy (RT) after BCS. Although some single-institutional studies have reported that mastectomy rates have recently increased, a recent population-based study reported that the rates of BCS have remained stable or slightly increased over the past decade in the United States. Both single-institutional and population-based studies have reported that CPM rates have markedly increased in recent years. On the other hand, unilateral mastectomy rates have decreased. Despite the potential benefit of RT after BCS, population-based studies indicate that an increasing number of women are not receiving RT after BCS, particularly high-risk women. These trends have important potential untoward consequences, including overtreatment for some patients and undertreatment for others. Several strategies are being developed to ensure adequate local therapy for breast cancer patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr MS2-1.
Abstract MS2-2: Nipple-Sparing Mastectomy with Nipple Areola Intra-Operative Radiotherapy: One Thousand and One Cases of a Five Years Experience at the European Institute of Oncology of Milan (EIO)
Authors: Petit J-Y
Published: April 2011

Background: in order to reduce mutilation, nipple-areola complex (NAC) conservation can be proposed for a treatment of breast cancer when mastectomy is indicated. To reduce the risk of retro areolar recurrence, a novel radiosurgical treatment combining subcutaneous mastectomy with intraoperative radiotherapy (ELIOT) is proposed. Methods: In a series of more than 1900 Nipple Sparing Mastectomies (NSM) performed at the European Institute of Oncology (IEO-Milan), 1007 (in which 37 bilateral), were registered from March 2002 to November 2007, for invasive carcinoma in 82% of the patients and in situ carcinoma in 18%. Clinical complications, aesthetic results, oncological and psychological results were recorded. A comparison was performed between the 843 patients who received ELIOT and the 208 who underwent delayed one-shot radiotherapy on the days following the operation.

Results: The median follow up time was 52 months (range 1.16-100.73) for a minimum follow up of a 6 months for 100% of the patients. The NAC necrosed totally in 40 cases (3,9%) and partially in 66 (6.5%) and was removed in 60 (5.5%). Twenty four infections (2.56%) were observed and 51 (4.85%) prostheses removed. The median rate of the patients for global cosmetic result on a scale ranging from 0 (worst) to 10 (excellent) was 8.

Evaluation by the surgeon in charge of the follow-up gave a similar result. Only 11% of the patients reported a partial sensitivity of the NAC. Of the 31 local recurrences (3%) 21 occurred close to the tumour site or in other quadrant, 7 close to the NAC corresponding to the radiation field and 3 Paget. Overall, 82 cases of metastases (8.1%) and 28 deaths (2.7%) were observed. No significant outcome difference was observed between the 843 patients receiving intraoperative radiotherapy (ELIOT) and 208 patients receiving delayed irradiation. LR rate of a series of 597 NSM with invasive carcinomas was 25 (4.18%) after a follow up of 59 months Our psychological analysis concluded that sixty eight per cent of patients were satisfied with their reconstructed breast and 97% were satisfied with the preservation of the NAC.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr MS2-2.
Abstract MS3-1: The Role of Providers in Breast Cancer Disparities
Authors: Keating NL
Published: April 2011

Recent research suggests that racial disparities in health care may be driven in part by differences in where minority patients seek care. Minority patients are more likely to receive care in lower performing hospitals and to be treated by physicians that are less well trained and have less access to important clinical resources than those treating white patients. We analyzed Surveillance, Epidemiology, and End Results (SEER)-Medicare to understand more about the influence of providers on care for older women with early-stage breast cancer.

In a first analysis, we assessed the hospitals where white and black women with early-stage breast cancer received care. We observed that a small number of hospitals treated the majority of black patients (e.g., 81% of black patients had surgery at 82 of the 481 (17%) hospitals). We found that black women were more likely than white women to undergo breast cancer surgery at hospitals with lower rates of radiation following breast-conserving surgery. This difference in site of surgery explains some of the racial disparities in receipt of definitive primary therapy for early-stage breast cancer.

In a second set of analyses, we assessed the role of distance, hospital racial composition, hospital safety net status, and other hospital characteristics on patient's choice of hospital. Preliminary analyses suggest that proximity to certain hospitals explains only a portion of the greater distribution of black breast cancer patients in lower-quality hospitals. Black women with breast cancer appear to seek care in hospitals that also care for greater numbers of black patients with other medical conditions. Additional analyses are exploring the influence of other hospital characteristics on choice of hospital.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr MS3-1.
Abstract MS3-2: Advances in Breast Cancer Risk Assessment, Screening and Prevention: Adapting the Lessons to an Underserved Latina Population
Authors: Weitzel JN
Published: April 2011

Breast cancer (BC) is the most common cancer and the leading cause of cancer death in Latina women. Mutations in BRCA genes are associated with 5% of all BC and a larger proportion of young women with BC. Genetic cancer risk assessment (GCRA) has the potential to identify persons at increased risk for cancer prior to the onset of disease, when early detection or prevention strategies would be most effective. Despite clinical studies documenting the efficacy of cancer risk reduction measures in high-risk individuals, low-income, underinsured or ethnic minority individuals have a disproportionate burden of cancer and limited access to GCRA. City of Hope Cancer Screening & Prevention Program Network outreach clinics were established in two regional indigent healthcare delivery systems. Consultations are facilitated by an experienced bilingual cancer risk counselor/physician team and risk management recommendations are given based on BRCA test results or empiric risk estimates. We observed a high prevalence of deleterious BRCA mutations (25–34%) among Latinas seen in a large network of high-risk clinics from Texas to Northern California, and also identified a unique recurrent large BRCA1 rearrangement of presumed Mestizo origin. We also established that the BRCA1 185delAG detected in several independent Latina families shared a common ancestral origin with Jewish carrier families. The presence of additional recurrent mutations led us to pursue ancestry informed strategies for more cost-effective BRCA analyses in underserved Latina populations. Our clinical studies indicate that underserved patients embrace the opportunity for GCRA services, attend their scheduled consultations, have a high level of participation in follow-up surveys and show a positive impact on cancer screening and prevention behaviors.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr MS3-2.
Abstract P1-01-06: How Often Does a Positive Sentinel Lymph Node Biopsy Prompt an Isolated Delayed Axillary Lymph Node Dissection?
Authors: Benson JR , Wishart GC , Forouhi P , Provenzano EN.
Published: April 2011

Background: Intra-operative nodal assessment can avoid delayed axillary lymph node dissection (ALND) in a proportion of sentinel lymph node biopsy (SLNB) patients. Several different methods are currently being practiced with no single one perceived as optimal in terms of performance, patient care, logistics and cost. Both frozen section and imprint cytology are inconsistent and of variable sensitivity compared to paraffin embedded H&E sections and have not yet been surpassed by molecular assays based on reverse-transcription technologies. Modern approaches to axillary management can contribute to reduction in absolute numbers of isolated completion ALND cases without intra-operative nodal assessment. Methods: A retrospective analysis was undertaken of 549 consecutive patients involving a total of 550 non-invasive (extensive or localised ductal carcinoma in situ with mass lesion) and invasive tumours measuring <5cm in maximum radiological size with clinically negative nodes (1 bilateral case). This group of patients were all eligible for SLNB according to unit guidelines. Those patients having SLNB before neoadjuvant therapy (32) or immediate breast reconstruction (IBR) (56) were excluded from further analysis together with 23 patients undergoing single stage axillary surgery (level I/II ALND) due to advanced age or co-morbidity. The remaining 438 patients were potentially liable for an isolated delayed completion ALND consequent to a positive SLNB. Most of these (84%) had an axillary ultrasound examination (368/438) with 58 proceeding directly to ALND based on positive nodal core biopsy (49), suspicious nodes with (6) or without (3) a negative biopsy.

Results: Amongst 381 cases of SLNB, 87 were node positive (22.8%) and proceded to completion ALND. Just over half of these had an isolated delayed ALND (50), whilst 37 patients had ALND combined with an additional surgical procedure (cavity re-excision; mastectomy with or without IBR). The recall rate for isolated ALND was 9.1% (50/549) when calculated as a percentage of all patients initially eligible for SLNB and 11.4% when the denominator was the number of tumours suitable for primary surgical treatment with SLNB or ALND based on axillary ultrasound (50/439). Within the authors’ practice, this represents a caseload for each surgeon of about 7 per annum.

Conclusion: Intra-operative node assessment may be more difficult to justify for all SLNB patients in the context of contemporary practices. A significant proportion of patients are either deselected for SLNB by axillary ultrasound (approximately one-third of node positive patients overall) or can have completion ALND performed alongside definitive or additional breast surgery. Intra-operative analysis may further reduce these low recall rates for isolated ALND but may not be cost-effective nor logistically feasible within many healthcare systems.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-06.
Abstract P1-01-07: Touch Imprint Cytology for Intraoperative Evaluation of Sentinel Lymph Node in Patients with Early-Stage Breast Cancer: A Five-Year Experience
Authors: Chen J-j , Yang B , Chen J-y , Liu Z-b , Huang X-y , Yang W-t , Xu W-p , Shao Z-M , Shen Z-z , Wu J.
Published: April 2011

Background: Accurate intraoperative diagnosis of sentinel lymph node (SLN) metastases enables the selection of patients for axillary lymph node dissection during the same operation and reduces the need for re-operation. Touch imprint cytology (TIC) serves as a main intraoperative assessment of SLNs in our institute for over five years. The purpose of the present study is to evaluate the clinical value of TIC as an intraoperative assessment for the diagnosis of SLN.

Methods: Patients treated for early-stage breast cancer between Feb-2005 and May-2010 enrolled in the study. TIC was routinely performed intraoperatively, the result of which was correlated with definitive histological assessments of serial section with Hematoxylin-Eosin staining. Subsequent immunohistochemistry staining with CK-19 and MUC-1 were performed for research purposes. The Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram was applied in this retrospective study to estimate probability of SLN involvement of each case. Results: A total of 1,077 patients with early-stage breast cancer enrolled in the study, and 3,048 SLNs were successfully harvested during the surgeries. Among those, 265 (24.6%) patients proved to have at least one SLN that was positive for carcinoma. Altogether, 397 (13.0%) involved nodes were removed from patients in the aforementioned patient pool. Based on the final pathology report, the sensitivity, specificity and overall accuracy of TIC was 83.4%, 99.0% and 95.2%, respectively on a per patient basis, and 78.3%, 99.4% and 96.7%, respectively on a per node basis. The sensitivity for macrometastasis and micrometastasis are 88.6% and 39.3%, respectively on a per patient basis, while 87.4% and 31. 3%, respectively on a per node basis. Of the patients included in this study, 98.7% had a positive SLN within their first three harvested SLNs. All the patients who were at a <10% chance of SLNs metastases according to the MSKCC nomogram were proved to be node negative by the final pathology. Conclusion: TIC is feasible and is able to detect macrometastasis in SLNs with an acceptable accuracy for clinical use in early-stage breast cancer patients while its ability to detect micrometastasis is limited. Limiting intraoperative TIC to the first three harvested SLNs in the diagnosis of SLN metastasis may make this diagnostic procedure significantly cheaper and easier for pathologists to perform. The MSKCC nomogram could be applied as a screening tool. Intraoperative assessment for SLNs, such as TIC, could be spared for patients with extremely low MSKCC scores (<10%).

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-07.
Abstract P1-01-10: Optimal Sampling Number of Sentinel Lymph Nodes in Invasive Breast Cancer: Results of 1,026 Sentinel Lymph Node Biopsies by Radioisotope
Authors: Choi J-E , Park S-Y , Jeon M-H , Kang S-H , Lee S-J , Bae Y-K.
Published: April 2011

Backgrounds: For isotope mapping, many authors defined the sentinel lymph node (SLN) as one containing isotope counts higher than the axillary background. Some defined the SLN by using a node/background ratio. However no study has sought to define optimal guideline, and the number of SLNs needed for precise detection of metastatic SLNs is still on debate. So, we intended to determine the optimal sampling number of SLNs. Patients and Methods: From January 2005 to December 2008, 1,026 patients with primary invasive breast cancer who received sentinel lymph node biopsy (SLNB) using radioisotope at Yeungnam University hospital were enrolled. During SLNB, the ex vivo isotope counts were measured for each SLN. And the number and metastatic status of harvested SLNs were investigated. We defined SLNs as lymph nodes that show isotope count more than 10 times compared with that of axillary background. Each SLN was labeled as S1 (highest isotope count), S2 or S3 and so on, in descending isotope count order. If SLN was positive for metastasis, completion axillary lymph node dissection was performed. Pathologic report was reviewed for analysis.

Results: Mean age of patients was 48.9 years (ranges, 22∼83 years) and the mean number of removed SLNs was 2.8 (ranges, 1∼11). Among 311 (311/1026, 30.3%) patients who had SLN metastasis, S1 is positive (S1+) in 258 patients (82.9%), S2 (S1-, S2+) in 40 patients (12.3%), and S3 (S1-, S2-, S3+) in 13 patients (3.9%), respectively. There was no metastasis in SLN defined as S4, S5 and so on. So, the sampling of S1 was sufficient for a positive diagnosis in 82.9% of these cases, additional sampling of S2 and S3 increased metastatic detection rate to 95.2% and 100%, respectively. Average number of sampling SLNs until detecting metastasis in S1, S2 and S3 is 1.24 (1∼4), 2.45(2∼4) and 3.46(3∼5), respectively.

Metastatic status of SLN and the corresponding percentage of patients on the basis of the order of radioisotope count

SLN=sentinel lymph node

Conclusions: We concluded that during sentinel lymph node biopsy using radioisotope, for accurate axillary lymph node staging, at least 3rd isotope-count-order of sentinel lymph node should be removed. Therefore the average number of SLNs needed for detecting metastasis in S3 is four.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-10.
Abstract P1-01-14: Intraoperative Injection of Technetium-99m- Dextran 500 for the Identification of Sentinel Lymph Nodes in Breast Cancer
Authors: Graudenz MS , Delazeri GJ , Xavier NL , Menke CH , Spiro BL.
Published: April 2011

Background: The intraoperative injection of radiocolloid before a sentinel node biopsy (SLN) in breast cancer has been recently described.The advantages of this approach would be precluding the performance of a scintigram, cost reduction and elimination of pain and anxiety related to the preoperative procedure.

Objectives: To evaluate the efficacy of intraoperative injection of Dextran 500-99m-Tc and to analyze whether different radiocolloid doses, breast volume and Body Mass Index (BMI) influence the migration time to the axilla.

Material and Methods: This is a prospective study of 74 SLN biopsies of breast cancer patients, stages T1N0 and T2N0. After anesthesia induction, patients underwent subareolar dermal injection of 0.5 to 1.5 mCi (18 to 55 MBq) of filtered Dextran 500-99m-Tc (0.22µl) in a volume of 5 ml along with 2 ml of blue dye.

Results: The probe identification rate was 98% (73/74 cases) and the medium radiocolloid dose used was 0.97 mCi ± 0.22. The radiocolloid migration time to the axila was 10 min and 43 s (± 5:43 s). An average of 1.66 lymphnodes were identified through the use of radiocolloid and 1.53 through the use of bue dye. Different radiocolloid doses did not modify migration time to SLN (p=0.73). However, larger breast volumes were associated with longer migration time to the axilla (Pearson Correlation 0.393 p< 0.01). The same correlation was observed with BMI (Pearson Correlation 0.469 p< 0.01).

Discussion: The intraoperative injection of Dextran 500-99m-Tc is efficient in the identification of SLN in breast patients. Higher BMI and larger breasts determine longer migration time, however injection of larger doses of radiocolloid do not reduce transit time to the axilla.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-14.
Abstract P1-01-15: Intraoperative Imprint Cytology Examination of Sentinel Lymph Nodes after Neoadjuvant Chemotherapy in Breast Cancer Patients
Authors: Monrigal E , Dauplat M-M , Durando X , Abrial C , Le Bouedec G , Mouret-Reynier M-A , Cachin F , Kwiatkowski F , Tchirkov A , Dauplat J , Penault-Llorca F , Gimbergues P.
Published: April 2011

Background: Intraoperative imprint cytology (IC) is one of several accurate, proved methods to detect tumor cells in sentinel lymph nodes (SLN) from patients with operable breast cancer. In patients treated by neoadjuvant chemotherapy (NAC), studies have demonstrated the feasibility and accuracy of SLN biopsy procedure. The aim of this study was to evaluate the validity of tumor cell detection using IC in SLN from patients who underwent NAC.

Material and methods: Patients with infiltrating breast carcinoma receiving NAC (n= 132) were studied prospectively. At surgery, SLN biopsy followed by axillary lymph node dissection was performed. Intraoperative SLN evaluation using IC was performed in 80 out of 132 patients (60%). In the same period, IC has been evaluated at random for 100 chemonaïve patients in the same institution.

Results: Sentinel lymph node metastases were correctly identified using IC in 58 of 80 (72%) patients. False negative results were observed in 21 patients. The overall sensitivity and specificity of IC for the identification of lymph node metastases was respectively 38.2% and 97.8%. The positive predictive value was 92.9% and the negative predictive value was 68.2%. In univariate analysis and multivariate logistic regression analysis, patients with micrometastases or ITC in SLN have 2.3 times higher risk of a false negative IC result than patients with macrometastases of the SLN (P= 2.1.10-4; RR= 2.3; 95% confidence interval [1.37-3.85]). For chemonaïve patient, sensitivity, specificity, PPV and NPV were respectively 47.4%, 98.8%, 90% and 88.9%.

Conclusion: The accuracy of intraoperative IC observed in our study is similar to that reported previously in patients without NAC, indicating that IC is a clinically acceptable method for intraoperative pathological examination of SLN for patients after NAC. Variations in sensitivity are related to the proportion of cases with micrometastases and ITC, as it was also shown in chemonaive patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-15.
Abstract P1-01-31: Axillary Recurrence Rate Is Associated with Sentinel Lymph Node Pathology Protocol
Authors: Bolster MJ , Pepels MJ , Bult P , Wauters CA , Schapers RF , Meijer JW , Strobbe LJ , van Berlo CL , Klinkenbijl JH , Wobbes T , Voogd A , Tjan-Heijnen VC.
Published: April 2011

Background Internationally, there is no consensus on the pathology protocol to be used to examine the sentinel lymph node (SN). At present, therefore, various hospitals use different SN pathology protocols, leading to different SN findings and subsequent surgical treatment strategies. Previously, we reported in a prospective registry study of 4 hospitals in the Netherlands, that ultra-staging led to more axillary lymph node dissections (ALND) (Bolster et al. Ann Surg Oncol 2006). This present study reports follow-up data of the patients who had a negative SN, so patients who did not undergo an additional ALND. The question was, whether ultra-staging and thus fewer patients not undergoing an additional ALND, is effective in that it reduces the risk of relapse.

Patients and Methods Patients from 4 hospitals (A, B, C, and D) were prospectively registered when they underwent a SN biopsy because of a cytological or histological proven invasive breast cancer. In hospitals A, B, and C, 3 levels of the SN were examined pathologically, whereas in hospital D at least 7 additional levels were examined. In the absence of apparent metastases with H&E examination, immunohistochemical examination was performed in all 4 hospitals. Patients with a positive SN, including isolated tumor cells, underwent an ALND. This analysis focuses on the SN negative patients, who did not undergo a completion ALND. In all cases a follow-up period of at least 5 years was guaranteed. Primary endpoint was 5-year regional recurrence rate.

Results Of 541 patients who underwent a SN procedure, 341 (63%) patients had a negative SN, and did not undergo an ALND. In hospital D fewer patients had a negative SN when compared to patients in hospitals A, B, and C (34% versus 71%, P<0.001). At 5 years follow-up, 9 (2.6%) patients showed a regional lymph node relapse. Five (1.5%) patients had an axillary lymph node recurrence and 4 (1.2%) patients a supraclavicular recurrence. In hospital D none of the patients had a regional recurrence, as compared to 9 (2.9%) cases of recurrence in hospitals A, B, and C. Conclusion We showed that patients who underwent a less intensified SN pathology protocol, with a reduced performance of ALND, had a slightly increased risk of recurrence. However, whether this justifies 37 additional lymph node dissections per every 100 patients can be questioned. Therefore, a SN pathology protocol as is used in most centers nowadays, with on average 3 levels per node, seems to be adequate.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-31.
Abstract P1-02-06: Tamoxifen, Flaxseed and the Lignan Enterolactone Increase Stroma and Cancer Cell Derived IL-1Ra, Decrease Tumor Growth and Angiogenesis in Estrogen Dependent Breast Cancer Explants
Authors: Dabrosin C , Lindahl G , Abrahamsson A , Saarinen N.
Published: April 2011

The proinflammatory cytokines IL-1α and IL-1β have been shown to promote tumor angiogenesis, which may be counteracted by the IL-1 receptor antagonist (IL-1Ra). A diet with high amounts of phytoestrogens such as flaxseed (Flax), genistein (GEN), and the mammalian lignan enterolactone (ENL) may affect breast cancer progression possibly in a similar fashion as the anti-estrogen tamoxifen. Both cancer cells and the tumor stroma may be targets for cancer therapy. Therefore, we set up a model with species-specific components of the microenvironment by establishing human breast cancers in nude mice and sampled released proteins by microdialysis. We show that tumors of mice treated with tamoxifen, fed Flax or ENL exhibited decreased in vivo release of IL-1β derived from the murine stroma and decreased microvessel density whereas dietary GEN had no effects compared to controls. Cancer cells released IL-1Ra were approximately five times higher compared with stroma derived and tamoxifen, Flax, and ENL increased these levels significantly whereas GEN did not. In vitro, estradiol decreased released IL-1Ra of breast cancer cells. ENL completely reversed this whereas tamoxifen further increased IL-1Ra levels. IL-1Ra had no effect on breast cancer cell proliferation in presence of E2 in vitro whereas endothelial cell proliferation was significantly decreased by IL-1Ra in a dose dependent manner. Finally, IL-1Ra therapy of tumor bearing mice opposed estrogen dependent breast cancer growth and decreased tumor angiogenesis. These data may provide insights into tumor-stroma mechanisms involved in estrogen effects on breast cancer progression and tamoxifen and dietary interventions against this disease.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-02-06.
Abstract P1-02-07: Real-Time Functional Imaging of Tumor Vascular Normalization by Anti-Angiogenic Agents
Authors: Xing HR , Zhang Q , Bindokas V , Shen J , Fan H , Hoffman RM.
Published: April 2011

Background: We describe here new technology that enables non-invasive imaging of normalization of tumor blood vessels by anti-angiogenic agents in real time.

Materials and Methods: Variable-magnification in vivo-fluorescence imaging as well as fluorescence tomography were used to visualize vessel normalization.

Results: Morphological changes in the same vessel prior to and after drug treatment were imaged with high resolution in real time. Differences in vascular responses to the mTOR inhibitor rapamycin and to an anti-VEGF antibody were functionally imaged. Tumor vessel normalization was demonstrated by significantly reduced leakiness and subsequent improved tumor delivery of Paclitaxel-BODPY as well as by normalized morphology. The tumor vascular pool agent, AngioSense750, was retained in tumors after both anti-VEGF antibody and rapamycin treatment as visualized by noninvasive fluorescence tomography. The anti-angiogenic therapy normalized vessels, which significantly enhanced the antitumor efficacy of Paclitaxel due to increased drug penetration throughout the tumor. Discussion: The optical imaging technology described here is thus a powerful real-tool imaging tool of functional and morphological tumor vessel normalization and its therapeutic consequences.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-02-07.
Abstract P1-03-07: Differential Effect of Specific p53 Mutations on Breast Cancer Growth and Response to Hsp90 Inhibition In Vivo
Authors: Appleyard VL , Murray KE , Coates PJ , Vojtesek B , Muller P , Hrstka R , Thompson AM.
Published: April 2011

Background p53 mutation influences breast cancer cell growth and patient prognosis. However, different p53 mutations impart specific functions to the mutant protein, including dominant negative or gain of function effects. Mutant p53 molecules R273H and R175H are commonly found in primary breast cancers and are present in the MDA-MB-468 and SKBR3 cell lines, respectively. To compare the direct effects of these two mutations in vivo in an identical cellular background, H1299 (p53-null) cells were constructed to express R273H or R175H p53 mutants. Methods

Thirty female SCID mice were injected subcutaneously with 106 H1299 (p53-null), H1299/R273H or H1299/R175H cells in DMEM + Matrigel (50:50) suspension. Some mice were treated with an Hsp90 inhibitor, which is required for correct folding of many oncogenic proteins. Results

Xenografts bearing R175H showed a mean lag phase (time between cell injection and tumors at exponential growth) of 21 days and a doubling time of 5 days, whereas tumors bearing H1299 (p53-null) or R273H mutation had a lag phase of 31 days with a doubling time of 7 days. Immunohistochemical examination demonstrated a highly heterogeneous pattern of p53 protein expression in the more aggressive R175H expressing cells compared with R273H expressing cells. Hsp90 inhibitor treatment reduced the growth of H1299 and R273H cells, but not R175H cells. Conclusions

The specific p53 mutations directly influence the rate of tumor growth and the p53 protein staining pattern on immunohistochemistry. The differential effects of specific p53 mutations should be considered when interpreting clinical data involving p53 mutation such as in the EORTC 10994 trial, with implications for prognostic determination of individual breast cancer patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-03-07.
Abstract P1-03-08: Targeting Neurotensinergic Receptors for Bone Cancer Pain Relief
Authors: Geneviève R , Lemire M , Belleville K , Beaudet N , Martinez J , Philippe S.
Published: April 2011

Metastatic breast cancer spreads principally to long bones like femur. The presence of breast cancer metastasis in bone microenvironment results in severe pain increasing with disease progression. Opioids, including morphine, are a standard for bone cancer pain management despite their adverse effects at high doses. Our aim here was to examine the effects of opioidergic-independent neurotensin (NT) receptor (NTS1, NTS2) activation in alleviating bone cancer pain in a new clinically relevant mouse model. To this end, neurotensinergic agonists (PD149163, JMV-2012 or JMV-431) were intrathecally administrated to C57BL/6 mice implanted with syngenic E0771 metastatic breast cancer cells in the femoral intramedullary canal. Compounds were analysed for touch-evoked (von Frey), forced movement-evoked (Rotarod) and ambulatory (dynamic weight bearing) pain 18 days following E0771 implantation. The intrathecal injection of PD149163, a NTS1-selective agonist, induced a marked decrease of touch-evoked pain reaching 64 ± 9%. On the Rotarod, PD149163 treatment failed to improve either time spent on the rotating cylinder or the visual pain score. The injection of a non-selective agonist, JMV-2012, reduced touch-evoked pain of 16 ± 5%, but was not efficient in reversing pain under a physical effort on the Rotarod. JMV-431, a NTS2-selective agonist, produced a significant reduction of touch-evoked pain of 70 ± 9% in cancer mice, which also spent more time (10 ± 13%) on the Rotarod and expressed less movement-evoked pain (97 ± 20%) than saline-treated cancer mice. However, acute spinal JMV-431 failed to restore ipsilateral weight bearing toward basal values. The analysis of spinal neuronal activity of mice injected with JMV-431 showed a significant reduction of 55 ± 6% of c-Fos expression in laminae V-VII of the ipsilateral horn 18 days post implantation. In conclusion, these results indicate that the NTS2 receptor represents a promising target for treating bone cancer pain. Further investigations of continuous delivery of NTS2-selective agonists at the central and peripheral levels are under way to evaluate the real potential of these compounds for prophylactic and curative treatments against cancer pain.

Supported by CIHR/Canadian Pain Society/AstraZeneca and Cancer Research Society grants.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-03-08.
Abstract P1-04-01: X-Linked Inhibitor of Apoptosis Protein (XIAP) Regulates TRAIL-Induced Apoptosis in Inflammatory Breast Cancer Cells
Authors: Allensworth JL , Aird KM , Murray MB , Devi GR.
Published: April 2011

TRAIL, a proapoptotic receptor agonist, is a promising tool for anticancer therapy due to its selective triggering of death receptor-mediated apoptosis in cancer cells while sparing the majority of normal cells. Overexpression of X-linked inhibitor of apoptosis protein (XIAP) has been identified as a major mechanism of TRAIL resistance as a result of its ability to inhibit caspase activity, the effector arm of apoptotic cell death. Previous studies in our laboratory in preclinical models of inflammatory breast cancer (IBC), a highly invasive and lethal subtype, have revealed that apoptotic dysregulation mediated by XIAP is a key factor in IBC pathogenesis and acquired therapeutic resistance to epidermal growth factor receptor (ErbB1/2) targeting agents. Characterization of TRAIL efficacy in IBC cell lines derived from primary tumors revealed that SUM149, a triple negative, EGFR activated cell line, is sensitive to TRAIL-induced apoptosis and exhibits a corresponding decrease in XIAP and an increase in caspase3 activation compared to TRAIL-resistant SUM190, ErbB2 overexpressing cells in which XIAP levels are unchanged by TRAIL treatment. Profile from an apoptotic proteomic array revealed that SUM190 cells have low basal levels of the TRAIL receptors DR4 and DR5 in comparison to SUM149 cells. Stable overexpression of XIAP in the TRAIL-sensitive SUM149 cells resulted in a two fold decrease in sensitivity to TRAIL with decreased caspase3 activation. Further, SUM149wtXIAP cells showed low levels of TRAIL receptor expression similar to the TRAIL-insensitive SUM190 line. Conversely, increased cell death was observed in SUM190 cells in which XIAP was knocked down using a lentiviral shRNA expression construct. In order to examine therapeutic strategies aimed at restoring function to the apoptotic pathways in IBC cells, we used the small molecule inhibitor Embelin to modulate XIAP action. Treatment of SUM149wtXIAP cells with Embelin in combination with TRAIL enhanced cell death compared to treatment with TRAIL or Embelin alone. Assessment of the interaction using a derivation of the Chou-Talalay method revealed a combination index of 0.054 in SUM149wtXIAP cells, which is indicative of strong synergism between the two agents. These results reveal that knockdown or antagonism of XIAP allows TRAIL to induce activation of effector caspases efficiently and establishes the feasibility of use of XIAP inhibitors to enhance therapeutic apoptosis in IBC therapy. Funded by American Cancer Society-RSG-08-290-01-CCE (GRD), predoctoral DOD BCRP award (KMA), and the Duke University Chancellor's Scholarship (JLA).

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-04-01.