bluuebunny/crossref_metadata_2025 huggingface dataset:
RIBBON-2: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial Evaluating the Efficacy and Safety of Bevacizumab In Combination with Chemotherapy for Second-Line Treatment of HER2-Negative Metastatic Breast Cancer.
Authors: Brufsky A. , Bondarenko I. , Smirnov V. , Hurvitz S. , Perez E. , Ponomarova O. , Vynnychenko I. , Swamy R. , Mu H. , Rivera R.
Published: December 2010

Background: Three prior Phase III trials (E2100, AVADO, and RIBBON-1) established the clinical benefit of adding bevacizumab (BV) to various chemotherapies (chemos) as first-line treatment for metastatic breast cancer (MBC). A previous Phase III study (AVF2119g) in patients with predominantly heavily pre-treated MBC, in which BV was added to capecitabine (Cape), resulted in a significant increase in objective response rate (ORR), but did not meet the primary endpoint for progression-free survival (PFS). The current study, RIBBON-2, was designed to evaluate the efficacy and safety of the addition of BV to chemotherapies used as second-line treatment for MBC.Methods: Patients were randomized in a 2:1 ratio to chemo+BV or chemo+placebo (PL). Key eligibility criteria included one prior cytotoxic treatment for MBC, ECOG performance status of 0 to 1, and HER2-negative or unknown status. Prior to randomization, investigators chose one of the following chemo agents: taxane (T; paclitaxel 90 mg/m2/wk for 3 of the 4 weeks; paclitaxel 175 mg/m2, nab-paclitaxel 260 mg/m2, docetaxel 75–100 mg/m2, all given q3wk), gemcitabine (G; 1250 mg/m2 on Days 1 and 8 q3wk), Cape (2000 mg/m2 Days 1–14 q3wk), or vinorelbine (V; 30 mg/m2/wk). BV or PL was administered at 10 mg/kg q2wk or 15 mg/kg q3wk, depending on the chemo regimen. The primary endpoint of the study was investigator-assessed PFS pooled across the chemo cohorts. Key secondary endpoints included overall survival (OS), PFS within individual chemo cohorts, ORR, and safety.Results: 684 patients (T, 304; G, 160; Cape, 144; and V, 76) at 211 sites in 19 countries were randomized between February 2006 and June 2008. Overall, the two study arms were balanced for patient characteristics at baseline. The study met its primary endpoint of PFS pooled across chemo cohorts and also demonstrated a 10% increase in ORR when BV was added to chemo. At the interim analysis for OS, the median durations were 18 mo for chemo+BV and 16.4 mo for chemo+PL (see table).Across all chemo cohorts the incidence of BV-related AEs was consistent with data from previous studies. Hypertension was the only BV-related AE consistently increased in the chemo+BV arm across all chemo cohorts.Conclusions: The addition of BV to chemotherapies used for second-line treatment of MBC led to a significant improvement in PFS. The AE profile of BV in the overall study population and across the chemotherapy cohorts was consistent with that previously observed. Additional analyses, including PFS for the individual chemo cohorts, will be presented.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 42.
Phase III Randomized Trial of Sunitinib (SU) vs. Capecitabine (C) in Patients (Pts) with Previously Treated HER2-Negative Advanced Breast Cancer (ABC).
Authors: Barrios C. , Liu M. , Lee S. , Vanlemmens L. , Ferrero J. , Tabei T. , Pivot X. , Iwata H. , Aogi K. , Brickman M. , Zhang K. , Kern K. , Martin M.
Published: December 2010

BackgroundC monotherapy is approved for pts with ABC who progress after anthracycline (A) and taxane (T) therapies. SU is an oral, multitargeted tyrosine kinase inhibitor that has demonstrated a single-agent response rate of 11% in heavily pretreated ABC.MethodsTo test the hypothesis that SU is superior to C, we compared the 2 agents in a multicenter, randomized, open-label, phase III trial of 700 pts. Eligible pts (≥18 yrs, ECOG PS ≤2) had HER2-negative ABC that recurred after A and T therapy in the (neo)adjuvant, metastatic, or locally advanced disease settings. Pts were randomized (1:1) to continuous daily dosing of SU 37.5 mg or to C 1,250 mg/m2 (1,000 mg/m2 in pts >65 yrs) twice daily on days 1–14 q3wk. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), patient-reported outcomes, and safety.ResultsAfter a pre-planned interim analysis showed that the primary endpoint would not be reached, the Independent Data Monitoring Committee recommended stopping trial enrollment for futility. Pts randomized to SU were offered alternative treatment (tx). As of March 2009, 464 pts were randomized to SU (n=231; mean age 52.7 yrs; 29 pts ≥65 yrs) or C (n=233; mean age 52.4 yrs; 44 pts ≥65 yrs). 22.9% vs. 35.6% of pts continued to receive SU and C, respectively. Tx was discontinued due to adverse events (AEs) in 10.8% of pts in the SU arm vs. 7.7% of pts in the C arm. Most common AEs leading to discontinuation of SU were neutropenia (3 pts) and hand–foot syndrome, congestive cardiac failure, epistaxis, and thrombocytopenia (2 pts each). C was discontinued due to neutropenia in 3 pts. Median PFS was 2.8 mos (95% CI: 2.4–3.9; 162 PFS events) vs. 4.2 mos (95% CI: 3.4–5.0; 135 PFS events) for SU vs. C, respectively (HR 1.473; 95% CI: 1.167–1.858; P<0.001). ORR for SU was 9.1% (95% CI: 5.7–13.6) vs. 12.9% (95% CI: 8.9–17.9) for C. CBR was 14.3% (95% CI: 10.0–19.5) for SU vs. 21.9% (95% CI: 16.8–27.8) for C. Other secondary endpoint analyses are ongoing.ConclusionsAlthough some pts continue to benefit from SU, these data suggest that SU is not superior to C given as monotherapy. The observed AE profiles were similar to those previously reported for SU and C. C was better tolerated than SU. SU cannot be recommended as monotherapy on this dosing schedule. Phase III studies with SU in combination with chemotherapy and other agents are ongoing in ABC.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 46.
CIRG/TORI 010: 10-Month Analysis of a Randomized Phase II Trial of Motesanib Plus Weekly Paclitaxel as First Line Therapy in HER2-Negative Metastatic Breast Cancer (MBC).
Authors: Mackey J. , Hurvitz S. , Crown J. , Forbes J. , Roché H. , Pinter T. , Eiermann W. , Kennedy M. , Priou F. , Provencher L. , Adrover E. , Pienkowski T. , Houé V. , Rupin M. , Martin M.
Published: December 2010

Background: We assessed, in a double-blinded placebo-controlled trial, the effect of adding motesanib (M), a small molecule antagonist of VEGF, PDGF and Kit receptors, to paclitaxel (P) as first line treatment of subjects with MBC. A P plus bevacizumab (B) open-label arm was included. The study was supported by Amgen Inc.Methods: 282 subjects with HER2-negative and measurable MBC were randomly assigned treatment with P 90mg/m2 on days 1, 8 and 15 in combination with blinded placebo (Arm A), blinded M 125mg once daily (Arm B) or open-label B 10mg/kg on days 1 and 15 (Arm C). Treatment was administered in 28-day cycles until disease progression, toxicity or consent withdrawal. The primary objective was to compare objective response rate (ORR: CR or PR) between Arm A and B. Treatment efficacy was assessed every 8 weeks according to RECIST version 1.0 and scans were centrally reviewed.Results: 277 subjects received study treatment. Subject characteristics at entry were balanced: median age was 55, 80% had hormone receptor positive tumors and 66% had received adjuvant chemotherapy. At this analysis, 10 months after last enrolled subject, 235 subjects had completed treatment (median duration: 6 cycles). The median cumulative dose of P was similar across the arms: 1530, 1455 and 1652 mg/m2 in Arms A, B and C, respectively. Subjects received a median cumulative dose of 179 mg/kg of B (Arm C) and a median daily dose of 111 mg of M (Arm B). The table displays the efficacy results and relevant differences in toxicity incidences:More adverse events were reported in Arm B compared to the other arms, mainly grade 3 and 4 gastrointestinal toxicities, hepatobiliary toxicities and hypertension. Infections and stomatitis were more frequently reported in Arm C. Venous thrombo-embolic events were similar across all three arms. Among serious hepatobiliary disorders, 5 subjects experienced serious cholecystitis or gallbladder enlargement: 4 of them were managed by surgery and 4 subjects could resume study treatment.The ORR favored Arms B and C as compared to Arm A, with 49%, 52% and 41% respectively but the difference between Arm A and B was not statistically significant (p=.31, adjusting for stratification factors). Stable disease lasting at least 24 weeks was reported for 34%, 36% and 33% of subject in Arms A, B and C respectively. The Progression-Free Survival (PFS) did not significantly differ between the three arms.Conclusion: The antitumor effect of P and M is comparable to P and B as treatment of subjects with HER2-negative MBC but P and M increases toxicities compared to the other arms.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 47.
Changes in [18F]Fluorothymidine Pharmacokinetics Following Capecitabine Treatment in Human Breast Cancer Detected by Positron Emission Tomography.
Authors: Kenny L. , Contractor K. , Stebbing J. , Al-Nahhas A. , Palmieri C. , Shousha S. , Aboagye E. , Coombes R.
Published: December 2010

Background: Pre-clinical models used by our group have demonstrated that thymidylate synthase (TS) inhibition leads to redistribution of the nucleoside transporter, ENT1, to the cell membrane and hence increases the tissue uptake of [18F]fluorothymidine (FLT).Methods: In this study we assessed, for the first time, the altered pharmacokinetics of FLT in patients following TS inhibition. We analyzed 10 lesions from 6 breast cancer patients by positron emission tomography (PET) before and after treatment with capecitabine.Results: Whereas drug treatment did not alter tumor delivery pharmacokinetic variables or blood flow, tumor FLT retention variables increased with drug treatment in all but one patient. The baseline average standardized uptake value (SUV) at 60 min, rate constant for the net irreversible transfer of radiotracer from plasma to tumor (Ki) and unit impulse response function (IRF) at 60 min were 11.11 x 10-5 m2/ml, 4.38 x 10-2 ml plasma/min/ml tissue and 4.93 x 10-2 /min, respectively. At 1 h after capecitabine, the SUV was 13.55 x 10-5 m2/ml (p=0.004), Ki 7.40 x 10-2 ml plasma/min/ml tissue (p=0.004) and IRF 7.40 x 10-2 /min (p= 0.002).Conclusion: FLT pharmacokinetics did not change in normal tissues suggesting that the effect was largely restricted to tumor (p=0.55). In summary, we have identified FLT-PET retention parameters that could be used in future early clinical studies to measure the pharmacodynamics of TS inhibitors, as well as for identifying patients who are unlikely to benefit from TS inhibition.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5003.
Molecular Alterations in Pleomorphic Lobular Carcinoma In Situ (PLCIS) of the Breast.
Authors: Chivukula M. , Brufsky A. , Carter G. , Chandran U. , Lyons-Weiler M. , Dabbs D.
Published: December 2010

Introduction: Pleomorphic lobular carcinoma in situ (PLCIS) is a rare distinct variant of lobular carcinoma in situ (LCIS) which is morphologically difficult to distinguish from high-grade ductal carcinoma in situ (DCIS). We performed microarray DNA analysis to characterize the genetic changes of this entity in order to determine if such changes were unique to PLCIS.Materials and Methods: 5 Pleomorphic (4 in situ and 1 invasive) and 4 normal non-paired breast tissues were analyzed for copy number changes using the Affymetrix 250K Sty array. Copy Number (CN) changes were detected by the Partek (Partek Inc, St Louis, MI) software. Data processing steps included GC content correction and segmentation to determine regions of amplifications and deletions.Results: Each sample demonstrated a unique pattern of CN changes with amplifications being more frequent than deletions, and between 25 and 66 changes per sample. Chromosomes 1, 11, 14, 16 and 8 exhibit the most frequent changes. Large deletions in chromosome 16q were seen in 4 out of 5 samples and amplification of regions of 1q in 4 out of 5 samples. Focal common amplifications, defined as less than 100kb in length, CN>5 and present in at least 3 samples, were seen in a number of regions including 8q23.1 containing the NUDCD1 gene (5/5 samples), 14q23.3 containing the GPHN (3/5 samples) gene, 12p12.2 containing the gene SLCO1B3 (3/5 samples), and 4p16.1.Discussion: Our results indicate that changes on chromosomes 1, 11, 14, 16 and 8 are frequently observed in pleomorphic lobular carcinoma (PLC) as well as PLCIS. Deletions in chromosome 16q and amplification of regions of 1q seen in our cases are associated with loss of e-cadherin and β-catenin expression and are the characteristic genetic abnormalities seen in classic lobular carcinoma. In addition, the characteristic 8q23.1, 14q23.3 and 12p12.2 reported in high grade DCIS were seen in our cases as well. PLCIS exhibits overlapping features with both classical lobular neoplasa and high grade DCIS.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5004.
Correlation between 18F Fluorodeoxyglucose (FDG) Uptake and Tumor Characteristics in Locally Advanced Breast Cancers.
Authors: Giacchetti S. , Groheux D. , Hamy A. , Hindie E. , Cuvier C. , Lehmann-Che J. , Lehmann-Che J. , de Roquancourt A. , Albiter M. , Marty M. , Moretti J. , Espie M.
Published: December 2010

Background: This study analysed the correlation between [18F]fluorodeoxyglucose (FDG) uptake, assessed by positron emission tomography (PET), and prognostic factors in locally advanced breast cancersMaterial and Methods: All locally advanced breast cancers seen at Saint Louis hospital and treated with neo-adjuvant chemotherapy (NAC) have a FDG PET after core needle biopsy and before chemotherapy. We correlated the tumor characteristics: T-stage, histological grade, estrogen and progesterone receptors, c-erbB2 over-expression (immuno-histochemistry determination) and P53 (determinate on frozen biopsies by the FASAYmethod) to FDG standardized uptake value (SUV max). The statistics tests used are student test (comparison of 2 means) and kendall correlation.Results: From June 2006 to April 2009, 91 patients with locally advanced breast tumors have both PET scan and frozen tissue before NAC. Median age at diagnosis is 48 (26-81) and 45 % are post menopausal.Conclusion: This study indicates that FDG-PET uptake is correlated with the phenotype of breast tumours. Over-expression of c-erbB2 does not influence FDG uptake. Triple negative tumours and p53 mutated tumors have a high initial SUV which can reflect their aggressiveness and their chemotherapy sensitivity. The knowledge of SUV uptake according to tumor characteristics allows a better understanding of the role of FDG-PET in the prediction of neoadjuvant chemotherapy response.Patients characteristicsPtes characteristicsNumber of patients (%)Tumor size: T2/T3/T438 (41)/32 (35)/21(23)Lymph nodes N0/N1/N232 (35)/46 (50.5)/13 (14 )Invasive ductal carcinoma/invasive lobular carcinoma/miscellaneous82 (90 )/5 (5 )/3 (3)Histological grade/ 1/2/37 (7 )/49 (54)/35 (38)ER + / ER-58 (64 )/33 (36)PR+ /PR-35 (38) /56 (61)C-erbB2 +++15 (16 )Triple negative22 (24 )P53 ( 64 ptes) mutated/wild type32 (50)/32 (50) 

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5010.
Comparison of Synchrotron Images of DCIS of the Breast with Their Pathologic Findings.
Authors: Park S. , Bong J. , Hong J. , Wang H. , Kim H. , Kim J. , Oh H. , Jheon S. , Huang J.
Published: December 2010

Background: Synchrotron radiation x-ray imaging have opened a new door to explore breast tissue below the micron scale providing detailed internal structures of the samples with a great magnification and an excellent resolution. Using phase contrast technique, we got monochromated synchrotron images of DCIS (Ductal Carcinoma In Situ) of the breast tissue section. To figure out relation with their optical microscopic features, we compared the synchrotron images of the DCIS with their histopathologic findings of the same stained section.Material and Methods: A x-ray microscope was installed on 1B2 beamline of Pohang Light Source, a third generation synchrotron radiation facility with operating energy of 2.5 GeV in Pohang, Korea. The x-ray energy was set at 11.1 keV, and the x-ray beam was monochromatized by a W/B4C monochromator. Zernike phase-shifter was adapted for phase contrast x-ray microscopy. Formalin-fixed 5µm-thick breast tissue sample was attached onto the Kapton film, and positioned 25 m away from the beam source. The synchrotron image of sample was converted into a visual image on the CsI(TI) scintillation crystal, and this visual image was captured by a full frame CCD camera. After scanning, we patched these images one and another to show the large area of the tissue section. For the comparative analysis with their synchrotron image, synchrotron-scanned breast tissue sections were stained, and the histopathologic findings of the samples were captured by image analyzer. The magnifying power of this microscope was 100x.Results: The monochromated x-ray microscopic images of DCIS of the breast tissue were obtained with a good resolution. These images revealed various structures of DCIS lesion with a good contrast and high visibility by phase contrast technique. They include prominent and intact periductal basement membrane - a hallmark of DCIS lesion, and stippled fine microcalcifications which were indistinct in the histologic section, and a shadow of intense peritumoral inflammatory cell infiltration. But the minute changes of each cancer cell showing the features of cancer tissue such as, cellular differentiation and nuclear grade, were not identified well.Discussion: The x-ray microscopic imaging of DCIS of the breast tissue section with synchrotron radiation showed a good correspondence with the histopathologic findings of their stained tissue sections. And the synchrotron image of DCIS had some unique radiologic features differentiating from histopathogic findings. Therefore the synchrotron images of the DCIS lesion appear to have a new possibility of use for the clinical and research purposes in near future.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5015.
The Optical Characteristic of Breast Cancer.
Authors: Ogura H. , Ohmae E. , Nasu H. , Teruya C. , Yamashita D. , Ueda Y. , Oda M. , Yamashita Y. , Sakahara H.
Published: December 2010

Objectives: The optical parameters of breast were measured by time-resolved spectroscopy additionally to optical mammography (O-MMG), which utilizes near-infrared light for the detection of abnormal breast tissue as a non-invasive and painless new breast imaging technique. Here we report the spectroscopic feature of the breast cancer tissue clarified by comparing the optical characteristic of cancer tissue with contra-lateral normal area.Materials and Methods: Absorption coefficient (μa), and reduced scattering coefficient (μs')of the breast tissue were measured using Time-Resolved Spectroscopy method, and analyzed by photon diffusion equation. We irradiated a pulsed laser of 760, 800,and 830 nm wave-length at multiple sites including a site just above the cancer by TRS-20SH (Hamamatsu Photonics K.K.). The clinical trial started in January 2007. A total of sixty breast cancer patients participated in the trial and written informed consent were obtained from all of the patients.Results: In 800nm wave-length, absorption coefficient (μa) of breast cancer tissue was significantly high, compared with contra-lateral normal breast area (cancer: 0.0759±0.052, normal: 0.0572± 0.034, p=0.02). The result was also the same in 760,and 830 nm. There was no difference in reduced scattering coefficient (μs') of breast cancer tissue compared with contra-lateral normal area (cancer: 9.049±01.345, normal: 9.521±1.492, p=0.07).Conclusion: Absorption coefficient (μa) of breast cancer tissue was significantly high compared with contra-lateral normal area.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5019.
Impact of Virtual MRI Sonography with Magnetic Navigation on Detecting Residual Tumors in Patients with Breast Cancer Who Undergo Neoadjuvant Chemotherapy; Initial Experience.
Authors: Nakano S. , Fujii K. , Yorozuya K. , Yoshida M. , Mouri Y. , Kousaka J. , Fukutomi T. , Kimura J. , Ishiguchi T.
Published: December 2010

Objective: The accurate evaluation of the extent of residual disease after neoadjuvant chemotherapy (NAC) for breast cancer appears essential for successful clinical outcomes. However, there are limited date about the success of achieving negative margins in breast conservation therapy. Recently, we have developed virtual MRI sonography with magnetic navigation (real-time virtual sonography; RVS). RVS can overlay high-resolution structural image taken by sonography with functional image reflecting vascular permeability taken by MRI of the same site in real time. The objective of our study was to determine the relative accuracy of RVS in detecting residual tumors after NAC.Materials and Methods: Between April 2007 and May 2009, 96 breast conservation therapy were performed for invasive ductal carcinoma at our hospital. Fourteen patients with stage IIA-IIIB palpable invasive ductal carcinoma were enrolled in a study investigating the effects of NAC on tumor imaging. All patients underwent mammography, sonography, MRI, and RVS before and after NAC. MRI was performed with a 1.5-T scanner in the supine position using a flexible body surface coil to achieve the same position as that used in sonography. Based on MRI results, the absence or presence of residual tumors was used to classify treatment response into a clinically complete response (cCR) or non-cCR, respectively. Nine patients received lumpectomy, and 5 received mastectomy. The surgical resection area was determined by RVS. Detection rate was determined for residual tumors with or without RVS. The pathologically complete response (pCR) was defined as no invasive carcinoma.Results: All index tumors were detected by sonography and MRI before NAC. After NAC, a cCR was seen in 5 (5 of 14, 36%) patients. MRI correctly diagnosed pCR in 4 (4 of 5, 80%) patients. Detection rate for residual tumors was 9% (1 of 11) for mammography, 33% (3 of 9) for sonography alone, 78% (7 of 9) for MRI, and 89% (8 of 9) for RVS. It was noteworthy that 5 (5 of 5, 100%) cases with cCR were accurately localized onto the body surface with supplementation using RVS combined with pre- and post-NAC imaging while we were checking sonography. Although surgical excision was incomplete in 5 (5 of 9, 56%) patients, all positive surgical margins were ductal carcinoma in situ.Conclusions: By using RVS, two different forms of diagnostic imaging can be integrated in real time and thereby complement each other. The present results suggest that RVS is a useful imaging technique for detecting residual tumors that have been associated with local recurrence after NAC.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5024.
High Sensitivity and Specificity of Digital Infrared Imaging for Breast Cancer Detection in Younger Women Undergoing Breast Biopsy.
Authors: Wishart G. , Campisi M. , Chapman D. , Shackleton V. , Iddles S. , Hallett A. , Britton P.
Published: December 2010

Background and aim: Recent published evidence suggests that digital infrared breast scanning may be a useful adjunctive tool for breast cancer detection. In this study we have assessed the effectiveness of digital infrared imaging captured using Sentinel BreastScan (Infrared Sciences Corp., Bohemia, NY, USA) and compared the computer-generated reports from this system with expert manual review of the images as well as a new software programme currently under development called NoTouch BreastScan.Methods: A total of 100 patients scheduled for breast biopsy (n=106), following detection of an abnormality via clinical examination or breast imaging were recruited to this research ethics committee-approved study. After obtaining informed consent all patients were imaged using Sentinel BreastScan, prior to their scheduled biopsy procedure in the Cambridge Breast Unit. The data for each patient was analysed in four different ways for comparison with final pathology findings as follows: 1. Sentinel screening report (score 0 = normal, 1-5 = abnormal); 2.Sentinel neural network (positive or negative); 3. Independent expert review (positive or negative); 4. NoTouch BreastScan artificial intelligence (score 0-3 = normal, 4-10 abnormal).Results: Sensitivity for the whole group using Sentinel screening (53%) and neural network (48%) was low compared to recently published data (97%), expert review (78%) and NoTouch (70%).Sensitivity and specificity results for NoTouch BreastScan by age group are shown in table1Sensitivity and specificity results for NoTouch BreastScan by age group <50 years, n=2150-70 years, n=73>70 years, n=12All patients, n=106Sensitivity78%72%42%70%Specificity75%37%N/A48% Conclusion: This study confirms acceptable sensitivity (72%) for breast cancer detection using NoTouch BreastScan in women under 70 years of age despite the data being captured with Sentinel. This sensitivity increases to 78% for women <50 years old and is combined with a marked increase in specificity (75%) in this group. These encouraging figures may increase even further when data is captured by the NoTouch software and studies are ongoing with this novel imaging system.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5025.
A Nomogram To Predict Breast Cancer Probability in Patients with Nipple Discharge.
Authors: Mazouni C. , Bonnier P. , Uzan C. , Haddad O. , Delaloge S. , Rimareix F. , Garbay J.
Published: December 2010

Background: Nipple discharge is a symptoms of breast disease that lead to the diagnosis of breast cancer in 5% of cases. Our objective was to develop a scoring system based on clinical and radiological factors to predict the risk of breast cancer (BC).Methods: Predictive factors of breast cancer were identified in a population of 90 women operated for unilateral nipple discharge, at Institut Beauregard, in France. A scoring system that gives individual probability of BC was developed based on univariate and multivariate logistic regression models. This model was validated in an external independent data set of 263 patients treated at Institut Gustave Roussy, in France.Results: The frequency of BC was 50% and 19.1%, respectively in the training set and in the validation. set. Factors associated with BC were age (p=0.04), presence of a clinical tumor (p=0,03), presence of a nodular lesion (p=0,03) or microcalcifications (p= 0.006) at mammography, in univariate analysis. In multivariate analysis. Only age (p= 0.03), microcalcifications (p= 0,007), or nodular lesion (p=0.06) at mammography were significance or tend to reach significance in multivariate analysis. Based on AIC, factors entered in the model were: age, clinical mass, abnormal images at mammography. The model has a good auc (76.6%). In the validation set, the auc was lower (66.6%).Conclusion: A clinico-radiological model can be built to predict BC in women with nipple discharge to help the decision-making and plan the suitable surgery. A further validation and testing of biological parameters might improve our model.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5031.
A Novel Tumour-Based Test To Identify Breast Cancer Due to BRCA1 and BRCA2 Mutations.
Authors: Eccles D. , An Q. , Jones L. , Tapper W. , Chelala C. , Iravani M. , McKay A. , Hammond V. , Durcan L. , Gerty S. , Strefford J. , Ferguson A. , Peock S. , Reis-Filho J. , Easton D. , Ashworth A.
Published: December 2010

Background: Family history and young onset are the usual indicators of an underlying genetic predisposition to breast cancer development. BRCA1 associated breast tumours are more likely to be ER negative and express “basal” markers, however most patients with ER negative/ basal marker positive breast cancers (especially young onset) do not have inherited BRCA1 mutations. BRCA1 and BRCA2 gene carriers may have novel treatment options available and may need to consider future cancer prevention strategies. Genetic counselling and germline mutation analysis remains a relatively expensive option that is not appropriate for most breast cancer patients.Aim: To design a sensitive and specific pathology based predictor that would improve identification of BRCA1 and 2 gene carriers.Method: We assembled a training panel of breast cancer tumour blocks from 67 BRCA1, 71 BRCA2 associated and 105 sporadic young onset cases (≤ 40 years at diagnosis). All gene carriers were diagnosed before 50 years and were matched to sporadic cases for ER status. Tissue micro arrays (TMAs) were assembled and subjected to immunohistochemical analysis with a panel of 18 antibodies. DNA was extracted from micro dissected tumour tissue and matched patient lymphocytes and subjected to high resolution tiling path microarray-based Comparative Genomic Hybridisation (aCGH). Using robust statistical approaches, regions significantly differentially lost, gained or amplified in BRCA1, BRCA2 and controls were identified. Probes for chromogenic in situ hybridisation (CISH) for amplified regions were generated.Results: Two differentially amplified clones in BRCA1 cases designated P1 at 3q25.31 and P2 at 3q25.2 and one in BRCA2 cases, P3 at 20q13.13, were identified and amplifications validated in the training set using CISH. Logistic regression analysis of the panel comprising CISH and IHC markers was used to develop the best predictor. The best predictor for BRCA1 gene carriers was a combination of P1, ER and HER2. This combination outperformed all combinations of immunohistochemical markers, including ER and basal markers; the Positive Predictive Value (PPV) was 87.5% and NPV 92% giving a Receiver Operator Characteristic (ROC) curve with an AUC of 0.92 (CI 0.88-0.97). The BRCA2 signature panel is currently being evaluated. These BRCA1 and BRCA2 predictor panels are being validated in a new set of TMAs comprising 223 tumours from the POSH study1.Conclusion: This tumour based predictor for BRCA1 and BRCA2 carriers may prove useful to identify gene carriers at low a priori chance of having a mutation, to direct BRCA1/2 targeted treatment approaches and to identify familial non BRCA1/2 cases that may be suitable for new gene discovery studies.1. Eccles D et al. BMC Cancer 2007; 7(1):160.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5032.
Outcomes of Guided Imagery (GI) in Patients Receiving Radiation Therapy for Breast Cancer.
Authors: Serra D. , Robertson-Paris C. , Chadha M. , Carper E. , Fleishman S. , Harrison L.
Published: December 2010

Background: There is an emerging recognition of the importance of Integrative Medicine in cancer care. We initiated a study evaluating the impact of GI on patients undergoing radiation therapy for breast cancer.Materials and Methods: A prospective, IRB-approved study evaluating the efficacy of GI among patients receiving radiation therapy for breast cancer was completed. Eligible patients had GI sessions with an Integrative Oncology Nurse (ION) and were given the tools and were trained techniques for self practice. The study endpoints include evaluating relaxation response to GI sessions using clinical variables that represent the level of an individuals stress and anxiety. These biofeedback measures included blood pressure (BP), respiration rate (RR), pulse rate (PR), and skin temperature (temp.) before and after the GI exercise. Further, the EQ-5D questionnaire, an established and validated tool for measuring health outcomes, was used for the subjective assessment. Patients completed the EQ-5D questionnaire prior to their first GI session (baseline data) and again at completion of radiation treatment. Patient feedback on their overall experience was collected at the end of the planned RT treatment through a satisfaction survey.Results: In all, 68 breast cancer patients have completed the protocol. The median age is 57 years. Median number of GI sessions with the ION was 4 (range: 1-6). In all cases, the parameters measured statistically significant improvement from baseline; median RR decreased from 19.6 per minute to 17.5 per minute; the mean drop of 4 beats/ minute in the pulse rate was observed. The mean drop in the systolic BP was 8.6mmHg, and the mean drop in the diastolic BP was 3.6 mmHg, and the mean skin temperature increased from 84.70F to 89.40F indicating increase in peripheral capillary flow secondary to a decrease in the sympathetic response. Results are summarized in Table 1. Overall 86% described the GI sessions as helpful, and 100% would recommend this intervention to others.Clinical VariablePrior to GI session (mean values)After GI session (mean values)p-valueRespiration rate19.617.5<0.001Pulse rate77.073.00.002Diastolic BP71.668.00.02Systolic BP124.3115.7<0.001Skin temp.84.7°F89.4°F0.007 Conclusion: The results of this study illustrate the positive impact of GI as measured through subjective and objective parameters. In improving the overall care of breast cancer patients there may be value to incorporating practices of Integrative Medicine.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5039.
Prospective Evaluation of Joint Symptoms in Postmenopausal Women Initiating Aromatase Inhibitors for Early Stage Breast Cancer.
Authors: Crew K. , Podolanczuk A. , Brafman L. , Awad D. , Hershman D.
Published: December 2010

Background: Aromatase inhibitors (AIs) are widely prescribed to postmenopausal women for the adjuvant treatment of hormone-sensitive breast cancer. However, musculoskeletal complaints, including joint pain and stiffness, are common, and can lead to nonadherence and treatment discontinuation. The aim of this study was to characterize the natural history of the AI-induced arthralgia syndrome.Methods: Postmenopausal women with stage I-III breast cancer initiating adjuvant AI therapy were enrolled. All patients completed the following questionnaires at baseline and every 3 months for a year: Modified Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and the Modified Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH). Higher scores reflect worsening joint symptoms. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES), where higher scores signify improved well-being. Hand grip strength was measured at each visit with a Martin dynamometer. Paired t-tests were performed to compare follow-up evaluations to baseline.Results: A total of 34 patients have been enrolled to date. Three-month data is available on 22; six-month data on 12. Median age: 60 (42-81); White/Black/Hispanic/Asian: 13/6/2/1; median BMI (kg/m2): 28 (20-43). Compared to baseline, there was a statistically significant increase in BPI pain severity and pain-related interference at 3 and 6 months. Significant changes in the M-SACRAH were seen as early as 3 months, but no difference in grip strength was detected. Participants reported significantly more endocrine-related symptoms on the FACT-ES at 3 and 6 months after initiating AI therapy.Conclusions: Treatment with adjuvant AI therapy is associated with significant worsening of joint pain and stiffness which was seen as early as 3 months and persisted at the 6 month evaluation. Understanding the natural history of this toxicity and validating appropriate measures to be used in interventions to prevent and treat AI-induced arthralgias are critical. Baseline3 Months6 Months Mean (SD)Mean (SD)P-value*Mean (SD)P-value*BPI-SF     Pain Severity (0-10)2.66 (2.52)3.85 (2.48)0.053.96 (2.42)0.02Pain Interference (0-10)1.40 (1.95)3.25 (2.53)0.022.60 (2.51)0.01M-SACRAH     Pain (0-200)47 (46)74 (52)0.0373 (65)0.08Stiffness (0-200)51 (45)85 (54)0.0383 (54)0.01Function (0-800)59 (74)129 (143)0.14168 (190)0.05WOMAC     Pain (0-500)67 (95)110 (126)0.19113 (135)0.06Stiffness (0-200)29 (40)45 (54)0.4643 (56)0.06Function (0-1700)271 (324)445 (400)0.15468 (373)0.06FACT-ES     Functional (0-28)20 (7)20 (6)0.9619 (6)0.15Physical (0-28)22 (5)20 (6)0.4420 (5)0.32Endocrine (0-72)58 (9)52 (14)0.0451 (11)0.01* Based on paired t-test, as compared to baseline.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5044.
Determining Issues of Importance for Patients with Breast Cancer: Results of a Web-Based Study in 1072 Patients To Enhance the Content Validity for the Development of a New Health-Related Quality of Life (Ql) Instrument, the Breast Cancer Symptom Scale (BCSS).
Authors: Weiselberg L. , Gralla R. , Horigan J. , Davis B. , Hollen P. , Petersen J. , Burg K. , Belland A.
Published: December 2010

Background:Identifying key issues for patients with malignancy is central to assessing QL and patient reported outcomes during all points of the illness trajectory. The involvement of patients in establishing content validity is crucial for instrument development. The conceptual model for the BCSS focuses on areas of importance for patients (Hollen, Supp Care Ca 1994).Methods:We used the established patient base of the web-based NexCura information resource to survey registered patients with breast cancer. Demographic stratifications included disease stage, age, menopausal status, time since diagnosis, prior/current treatment with surgery, RT, chemotherapy, hormonal, targeted, and CAM approaches. 1072 patients (median age 53, 65% stage I, 43% > 2 years since diagnosis) completed the anonymous web-conducted survey. Patients ranked 21 issues on a 5-point scale, assessing the importance of each item. Issues included general, physical, functional, psychosocial and summative items.Results:The 9 highest ranked items are seen below. Results are described by the percent of patients choosing the top category (very important) and the top 2 importance categories. The five lowest ranked items dealt with appetite, breast-specific issues, hot flashes and sexuality. Ratings by breast cancer subsets (newly diagnosed, on treatment, NED, hormonal or non-hormonal treatment, metastatic disease, survivors) showed some differences compared with the whole group.[table1]N=1072Very ImportantVery Important +ImportantGood QL82%99%Maintaning independence75%97%Able to sleep69%97%Able to concentrate65%97%Perfrom normal activities62%97%Being fatigued61%95%Having depression51%85%Being anxious47%85%Having pain46%80% Conclusions:These results represent one of the largest surveys of concerns expressed by patients with breast cancer and support using computer-assisted technology to assess such information for rapid input of large patient samples. This study gives strong support for content validity for the BCSS and provides data on which to base separate QL instruments for specific breast cancer settings.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5048.
How Important Is Cognition for Women with Breast Cancer? Results of a Web-Based Study of 1071 Breast Cancer Patients Used To Augment Content Validity of the Breast Cancer Symptom Scale (BCSS) a New Health-Related Quality of Life Instrument.
Authors: Shapira I. , Gralla R. , Davis B. , Petersen J. , Hollen P. , Horigan J. , Belland A. , Burg K. , Carleton J.
Published: December 2010

Background:Cognitive difficulties, such as loss of memory or ability to concentrate, have been associated with chemotherapy and other treatments for breast cancer. Causes for intellectual impairments have been proposed, including biological and psychological factors, however, strong evidence is lacking. Regardless of the cause, it is important for caregivers to appreciate, which cognitive impairments most concern their patients. As part of this survey, we sought the opinions of women with breast cancer to ascertain how these women rated the ability to concentrate among 21 major issues.Methods:We utilized the established patient base of the web-based NexCura information resource to survey registered patients with breast cancer. Demographic stratifications included disease stage, age, menopausal status, time since diagnosis, prior/current treatment with surgery, RT, chemotherapy, hormonal, targeted, and CAM approaches. 1071 women (median age 53, 65% stage I, 43% > 2 years since diagnosis) completed the anonymous web-conducted survey. Patients ranked the importance of 21 issues on a 5-point scale. Issues included general, physical, functional, psychosocial and summative items.Results:Of all 21 items, the 1071 women ranked the ability to concentrate as one of the four most important factors, as determined by those who rated it in the top category (very important, 65%) and the top 2 importance categories (97%). It followed only overall quality of life in the “very important” category, and was tied with maintaining independence and the ability to sleep in the sum of the top 2 importance categories. Analysis is being conducted to determine if ratings by breast cancer subsets (newly diagnosed, on treatment, NED, hormonal or non-hormonal treatment, metastatic disease, survivor-status) will differ compared with the whole group.Conclusions:Interference with concentration can affect nearly every aspect of functioning and quality of life, and can have an impact on quality decision making. Regardless of whether causes of cognitive impairment have supporting evidence, caregivers should be aware of the level of importance of concentration to patients with breast cancer and report symptoms related to executive function.Our results from one of the largest groups of breast cancer patients surveyed to date support the belief that women value the ability to concentrate most highly.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5049.
Effect of Density and Altered Structure of Adipose Stromal Cells on Breast Cancer Initiation.
Authors: Ghosh S. , Walter M. , Sitai L. , Hornsby P. , Hu Y. , Li R.
Published: December 2010

Increased adiposity is strongly associated with higher risk of estrogen-receptor positive postmenopausal breast cancer and increased mortality of breast cancer. Adipose stromal cells (ASC) play critical role in both development and metastasis of cancer as well as initiation of the disease. Within tumor microenvironment role of ASC is well studied, however, its role in initiation of the disease is less understood. In this study we uncovered novel function of ASC in both estrogen-dependent and independent cancer development. We showed that ASC induces aromatase, a key enzyme in estrogen biosynthesis, under the influence of cell density-stimulated shape change mechanism in cancer-free individuals. The activation of aromatase transcription is mediated by IkB kinase b (IKKb), a kinase previously known for its cancer-promoting activity in tumor cells. Activation of IKKb leads to elevated expression of transcription factor C/EBPb, which binds to and stimulates two breast cancer-associated promoters of the aromatase gene. We also show that shape-induced estrogen production in ASCs can stimulate estrogen-dependent transcription in ER-positive breast tumor cells. We developed a xenograft model that supported our in vitro observation.Here we further showed that density-driven ASCs significantly stimulated migration and invasion of ER-negative breast cancer cells in vitro and tumor invasion in a co-transplant xenograft mouse model. Our study also identified cofilin-1, a known regulator of actin dynamics, as an important determinant for the stimulatory activity of ASCs. The cofilin-dependent pathway controled the production of interleukin 6 (IL-6) in ASCs. Depletion of IL-6 from ASC-conditioned medium abrogated the stimulatory effect of ASCs on the migration and invasion of breast tumor cells. Thus, our study revealed how ASC, under an altered cellular architecture, may contribute to the breast cancer risk in obesity and high breast density.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 505.
Post Operative Analgesia for Breast Surgery: Intercostal Nerve Block Versus Subcutaneous Infiltration.
Authors: Syed A. , Devkaran A. , Mehta S. , Michail M. , Bradpiece H.
Published: December 2010

BackgroundPost operative analgesia is often underestimated in breast surgery resulting in long term sequelae. Opiates and epidural analgesia may produce complications and limits early rehabilitation. We compare the effects of intercostal nerve block with subcutaneous infiltration as post operative analgesia in breast surgery.MethodsAll patients who undergo breast surgery were assigned to two groups. They either receive intercostal nerve block or subcutaneous infiltration of 0.5% bupivacaine at the end of surgery. Pain score using visual analogue scale and the total amount of morphine consumption were recorded. Personnel taking measurements were kept blind.ResultsThere were 70 patients included in the study. Of these, three patients (two from Group A and one from Group B) were excluded because of post operative haematoma and drain related complications. 33 patients had intercostal nerve block and 34 patients received subcutaneous infiltration. The groups were comparable with respect to age and type of breast surgery. There were significant differences in the visual analogue pain scores at the early post operative period in the study group (P value of < 0.05).Table 1Pain ScoreGroup A Median (range)Group B Median (range)No. of patientsP valueWith in 4 hr of surgery2 (1-8)2 (1-9)330.7521st post op 8am2 (1-6)3 (1-8)330.0091st post op 6pm2 (1-6)2 (1-10)330.0112nd post op 8am1 (1-5)2 (1-8)120.2442nd post op 6pm1 (1-4)1.5 (1-5)110.2213rd post op 8am1 (1-4)1 (1-6)90.1373rd post op 6pm1 (1-7)2 (1-4)90.347 ConclusionsWe have demonstrated in our study that intercostal nerve block provides effective post operative analgesia in breast surgery patients. The accessibility of intercostal nerves in the operative field makes blockade feasible. Contrary to the misconception, incidence of pneumothorax is very rare. It should therefore be used more widely in view of its simplicity.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5052.