bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PD07-08: Zoledronic acid specifically inhibits development of bone metastases in the post-menopausal setting – evidence from an in vivo breast cancer model
Authors: Holen I , Wang N , Reeves KJ , Fowles AM , Croucher PI , Eaton CL , Ottewell PD 
Published: August 2014

Abstract
Background: A number of recent clinical trials have suggested that the benefits of adjuvant bone targeted treatments on risks of recurrence or death in early breast cancer are restricted to women with established menopause. We have used a model system that mimics pre- and post-menopausal status to investigate the effects of zoledronic acid on breast tumour growth in bone, demonstrating a differential anti-tumour effect in these two settings.
Methodology: Tumour growth was assessed by in vivo imaging following intra-cardiac inoculation of luciferase expressing MDA-MB-231 breast cancer cells in 12-week old female Balb-c nude mice. Animals underwent ovariectomy (OVX, mimicking the post-menopausal setting) or a sham operation (mimicking the pre-menopausal setting) 7 days after tumour cell implantation (n = 10/group). In treatment experiments, OVX and sham operated animals received either saline or 100ug/kg zoledronic acid (ZOL) weekly s.c. from day 4. Effects on bone were assessed by uCT analysis, bone histomorphometry and measurement of serum bone markers. Presence of tumour cells in bone was detected by multiphoton microscopy.
Results: OVX induced significant bone loss compared to sham within 2 weeks, which was completely inhibited by ZOL. Tumour growth was detected in the long bones of 29% of animals in the sham group on day 35 following tumour cell inoculation, and this was not affected by ZOL treatment. In contrast, 83% of the OVX animals had detectable tumours in the long bones, demonstrating that OVX mediated changes to the bone microenvironment that stimulated tumour growth. Crucially, this OVX-induced increase in tumour growth was completely prevented by weekly ZOL treatment, with only 17% of animals in the OVX+ZOL group having detectable bone tumours compared to 83% in the OVX+saline group. Multiphoton microscopy revealed that numerous individual tumour cells were present in long bones of animals in the OVX+ZOL group, supporting that ZOL acts by inhibiting an OVX-mediated trigger of tumour cell proliferation.
Conclusions: Our data are in agreement with those reported from clinical trials of adjuvant zoledronic acid, showing an anti-cancer effect exclusively in the post-menopausal setting. This is the first demonstration that zoledronic acid prevents tumour progression in bone specifically through inhibition of OVX-induced proliferation of tumour cells resident in the bone marrow.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-08.
Abstract S2-2: Sentinel Lymph Node Biopsy Before or After Neoadjuvant Chemotherapy - Final Results from the Prospective German, multiinstitutional SENTINA-Trial -
Authors: Kuehn T , Bauerfeind IGP , Fehm T , Fleige B , Helms G , Lebeau A , Liedtke C , von Minckwitz G , Nekljudova V , Schrenk P , Staebler A , Untch M 
Published: August 2014

Abstract
Background: The optimal timing for sentinel lymph node biopsy (SLNB) in the neoadjuvant setting is still unclear. Evidence for both, feasibility (detection rate, DR) and accuracy (false negative rate, FNR) of SLNB before and after primary systemic treatment (PST) is restricted to monocentric and/or retrospective trials. The success rates for SLNB are particularly unclear for patients who are downstaged from a cN1 to a ycN0 status.
Material and Methods: The German SENTINA (SENTInel NeoAdjuvant) trial is a 4-arm prospective multicenter cohort study designed to evaluate a specific algorithm for the timing of a standardized SLNB procedure in patients, who undergo PST and to provide reliable data for the DR and FNR in different settings. Patients were categorized into four treatment arms according to the clinical axillary staging before and after chemotherapy. Patients with a cN0 status underwent SLNB prior to PST and were categorized as arm A and B: If the SLN was histologically negative no further axillary surgery was performed after PST (arm A), whereas in case of histologically positive SLN status, a second SLNB and axillary dissection (AD) was performed after PST (arm B). Patients with a cN1 status prior to PST underwent no axillary surgery prior to PST and were stratified as arm C and D: If patients converted to cN0 after PST, SLNB and AD were performed (arm C); patients presenting with cN1 status after PST underwent classical AD (arm D).
Results: 1737 eligible patients from 103 institutions entered the trial. From these 662 patients were classified as arm A, 360 pts as arm B, 592 pts as arm C and 123 pts as arm D.
The DR for SLNB was 1013/1022 (99.1%) before PST (arms A and B), 474/592 (80.1%) in Arm C (after PST), and 219/360 (60.8%) in arm B (after prior SLNB and PST) (p &lt; 0.001). 226/474 pts (47.7 %) in arm C with a detected SLN after PST had a positive and 248 (52.3 %) had a negative axillary status. The SLN was false negative in 32 pts (14.2 %, 95% CI 9.9%–19.4%). From 219 patients in arm B with a detected SLN after PST 64 (29.2 %) had a positive and 155 (70.8 %) a negative axillary status. The SLN was false negative in 33 pts (51.6 %, 95% CI 38.7%–64.2%).
Conclusion: In patients, who convert from a positive to a negative cN stage during PST the DR for the SLNB is significantly lower compared to patients, who undergo SLNB prior to any other treatment. The FNR is less favorable compared to primary SLNB. Prior systemic and/or surgical treatment significantly impairs the success rates of SLNB.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S2-2.
Abstract OT3-1-06: CIBOMA/2004-01_GEICAM/2003-11: A randomised phase III trial assessing adjuvant capecitabine (Cap) maintenance therapy after standard chemotherapy for triple-negative early breast cancer (EBC)
Authors: Barrios CE , Lluch A , Ruiz-Borrego M , Bines J , Torrecillas L , Carrasco E , Segalla JGM , Ruiz A , Garcia-Saenz JA , Torres R , De la Haba-Rodriguez J , Garcia-Martinez E , Morales S , Gomez H , Salvador-Bofill J , Hernando A , Martin M 
Published: August 2014

Abstract
Background: The ideal adjuvant treatment of triple negative EBC remains to be defined. CIBOMA/2004-01_GEICAM/2003-11 is a multinational randomized phase III trial exploring adjuvant Cap after the conclusion of conventional chemotherapy in triple-negative EBC patients.
Materials and Methods: Patients with operable, node-positive (or node-negative with tumour diameter ≥1 cm), hormone receptor-negative, HER2-negative EBC that have received 6–8 cycles of standard anthracycline and/or taxane-containing chemotherapy in the (neo)adjuvant setting (doxorubicin–cyclophosphamide x 4 allowed for node-negative disease), followed by radiotherapy (if indicated) are eligible. After central confirmation of triple negativity by immunohistochemistry, patients were randomised to either 8 cycles of Cap (1,000 mg/m2 bid, d1–14 q21d) or observation. Stratification factors: centre, prior taxane (yes vs. no), involved nodes (0 vs. 1–3 vs. ≥4) and phenotype (basal vs. non-basal). The primary endpoint is disease-free survival (DFS). Secondary endpoints include 5-year DFS, overall survival and safety. An optional pharmacogenetic sub-study will explore polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase in relation to efficacy and tolerability of Cap.
Present Status: Recruitment of 876 randomized patients was completed in September 2011. Statistical assumptions: expected 30% reduction in the risk of recurrence at 5 years (64.7% to 73.7%, HR 0.701), power of 80% and 0.05 two-sided significance level. Final efficacy analysis will be triggered by 255 events. Baseline characteristics are well balanced and shown in the table below. 75.0% of the patients completed the 8 cycles of adjuvant Cap.
Baseline patients characteristics Capecitabine (n = 448)Observation (n = 428)Median Age, years (range)51 (20-79)50 (24-83)Basal Phenotype,%70.772.2Histology,% Ductal87.786.1Lobular1.82.3Other9.811.4Unknown0.70.2Grade,% 13.32.8218.119.0371.969.6Not determinable6.08.4Unknown0.70.2Chemotherapy received,% Adjuvant (only)78.982.2Neoadjuvant (only)15.615.0Adjuvant + Neoadjuvant4.22.6Unknown1.30.2Postmenopausal,%69.267.3Prior Chemotherapy Agents,% Anthracyclines without taxanes32.132.2Anthracyclines and taxanes67.267.6Unknown0.70.2
Conclusions: This randomized phase III adjuvant trial in triple negative EBC patients has completed accrual and event follow up is ongoing. The trial is sponsored by CIBOMA/GEICAM.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-06.
Abstract P1-02-04: Array based resolution of HER2 amplification status in breast carcinomas displaying apparent chromosome 17 aneusomy
Authors: Portier BP , Wang Z , Minca E , Lanigan C , Downs-Kelly E , Tubbs RR 
Published: August 2014

Abstract
Background:
Molecular inversion probe (MIP) arrays offer high-quality copy number and genotype data with whole-genome coverage and high resolution of cancer related genes. The MIP array assay is specifically designed for use with Formalin Fixed Paraffin Embedded (FFPE) tissue due to its design which utilizes hybridization of short sequence inversion probes. In this study, we performed MIP array analysis on a cohort of breast carcinomas with putative chromosome 17 aneusomy identified by HER2/CEP17 dual probe FISH. We hypothesized that MIP array performed on cases with chromosome 17 aneusomy would allow HER2 amplification status resolution and provide additional clinically actionable data on genes with predictive and prognostic significance.
Design:
DNA was extracted from formalin fixed paraffin embedded tissue (Qiagen,Valencia, CA) from invasive breast carcinomas following macrodisection. Breast carcinomas utilized in this study segregated into three groups: 1) Aneusomic 2) Monosomic, and 3) Eusomic cases as determined by FISH utilizing a centromere 17 reference probe (PathVysion; Abbott Molecular). Matched patient normal lymph nodes were performed for a subset of cases from each group. MIP-array data was collected using the Affymetrix OncoScan™ array (Affymetrix, Santa Clara, CA). Analysis of array data was performed using Nexus software v6 (BioDiscovery, Inc., Hawthorne, CA).
Result:
Array-based detection of HER2 amplification in aneusomic breast carcinomas showed 100% concordance with single probe (HER2) FISH. However, based on genomic profiling, these cases showed great variability in regions of aneusomy along chromosome 17. In our aneusomic cohort, one region of chromosome 17 showed conserved eusomy status. This region was utilized for both array and FISH based ratio to resolve HER2 amplification status in 18 of 22 (82%) of cases. In addition to HER2 status resolution by MIP array, gains and losses in genes involved in modulating therapy were also identified, using this single assay.
Conclusion:
Use of MIP array-based genotyping as a single reflex assay in breast carcinomas with apparent chromosome 17 aneusomy resulted in HER2 amplification status resolution. In addition, use of this assay in our aneusomic cohort resulted in identification of a highly conserved region of chromosome 17 that is highly resistant to gains or losses in ploidy. The “D17S122” region was confirmed by FISH and use of a HER2/D17S122 ratio, allowed resolution of HER2 amplification status. In addition to HER2 status resolution and copy number data, MIP Array also provided comprehensive genomic coverage for analysis of non EGFR family genes potentially important for prognosis and therapy response prediction.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-02-04.
Abstract P2-15-04: Trastuzumab re-treatment following adjuvant trastuzumab and the importance of distant disease-free interval: The HERA trial experience
Authors: Metzger Filho O , Procter M , de Azambuja E , Krieguer M , Gelber RD , Piccart M 
Published: August 2014

Abstract
Background: Trastuzumab (T) forms the backbone of the current first-line treatment of advanced HER2+ breast cancer. In the present study we sought to evaluate the impact of the time interval between the end of adjuvant trastuzumab and distant recurrence (TDRI), upon a) overall survival (OS), b) the duration of trastuzumab-based regimens (T) in the advanced setting.
Patients & Methods: a) The first hypothesis involved 187 pts on HERA treated with adjuvant T and diagnosed with distant recurrence after the scheduled treatment period of 1 year at 4 years median follow-up. The impact of TDRI on OS from distant recurrence was evaluated in a Cox model adjusted for tumor size, nodal and hormone receptor status at time of enrollment into the HERA trial. b) The second hypothesis involved 90 patients retreated with T in the metastatic setting. A questionnaire was sent to investigators retreating pts with T upon distant recurrence; 144 of 156 questionnaires were returned (93%), and 90 pts were selected based on available clinical information and consent for subsequent studies (14 pts were randomized to observation and received adjuvant trastuzumab after crossover).
Results: a) There was no statistically significant relationship between TDRI following 1yT and OS from distant recurrence: HR 0.99, p = 0.46; HR 0.99, p = 0.27 from the stratified and unadjusted Cox proportional hazard models, respectively. The median OS from distant recurrence was numerically longer among pts with a TDRI of ≥ 12 months (n = 103) than &lt; 12 months (n = 84) but not statistically significant (23.7 vs. 17.8 months, p = 0.47). b) The median duration of T-based regimens for metastatic disease was 8.8 months (n = 88), 9.4 months in the ER+ cohort (n = 36) and 8.8 months in the ER- cohort (n = 52); (n = 2, missing). Sites of first distant recurrence and subsequent disease progression for the 90 pts were hierarchically distributed as below.
First distant recurrence n (%)Subsequent progression n (%)CNS6 (6.7%)22 (24.4%)Visceral45 (50.0%)39 (43.3%)Skeletal25 (27.8%)9 (10.0%)Soft Tissue14 (15.6%)9 (10.0%)No event-11 (12.2%)
Conclusions: In the HERA trial, TDRI following 1yT did not impact on OS from distant recurrence in pts experiencing distant disease recurrence. This may be due to the benefit of anti-HER2 regimens in subsequent lines of therapy. Although our sample size is limited, the present analysis suggests that pts experiencing a shorter interval (≤ 12 months) from the end of adjuvant trastuzumab to distant recurrence derive similar benefit from trastuzumab-containing regimens in the metastatic setting when compared to the cohort with an interval &gt; 12 months. CNS relapse in HER2-postive breast cancer remains a clinical problem.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-15-04.
Abstract P3-12-06: Statin use and outcome among breast cancer patients treated with neoadjuvant systemic chemotherapy
Authors: Chavez-Mac Gregor M , Lei X , Litton JK , Melhem-Bertrand A , Giordano SH , Masuda H , Ueno N , Gabriel HN , Valero V 
Published: August 2014

Abstract
BACKGROUND: Statins are cholesterol-reducing agents that affect intracellular pathways associated with tumorigenesis and inflammation. Preclinical studies have demonstrated that statins have anti-tumor effects and epidemiological studies have suggested that the use of HMG-CoA-reductase inhibitors is associated with improved long-term outcomes among breast cancer patients. In this study we sought to evaluate the effect of statins in the pathologic complete response (pCR) and survival outcomes among breast cancer patients receiving neoadjuvant systemic chemotherapy (NST).
METHODS: Retrospective study including patients diagnosed between 1995-2007 with invasive primary breast cancer. All patients received neoadjuvant systemic chemotherapy. Use of statins during NST was identified by review of medical records. We compared pCR rate, relapse-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) between statin-users and non-users. pCR was defined as no evidence of invasive carcinoma in the breast and axillary lymph nodes at the time of surgery. Descriptive statistics and Cox proportional hazards model were used in the analyses.
RESULTS: From the 1449 patients included, 74 (5.11%) were treated with statin during NST. Statin users were more likely to be older, overweight/obese and more likely to be also treated with beta-blockers or metformin. No differences in pCR were observed according to statin use (16.2% vs 17.6% p = 0.75). In the multivariable model, the use of statin was not an independent predictor of pCR. With 55 months of follow-up (415 recurrences and 359 deaths), the 5-year RFS was 82% in the statin-treated patients and 70% in the non-statin treated group (p = 0.03), no differences were seen in DSS or OS. Subset analyses according to tumor subtype demonstrated patients with hormone receptor-positive tumors treated with statins had better 5-year RFS (93% vs 76%; p = 0.01). In the multivariable model, no association was observed between statin use and outcome.
CONCLUSIONS: In our cohort of patients, statin use during NST was not independently associated with pCR, RFS, DSS and OS. Further studies with larger number of statin-treated patients are warranted to clarify the role of HMG-CoA reductase inhibitors in the treatment of breast cancer patients. In addition future studies should evaluate the effect of prolonged statin use and take the different type of statin subtype into account.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-12-06.
Abstract PD1-3: Ph1b study of the PI3K inhibitor GDC-0032 in combination with fulvestrant in patients with hormone receptor-positive advanced breast cancer
Authors: Juric D , Saura C , Cervantes A , Kurkjian C , Patel MR , Sachdev J , Mayer I , Krop IE , Oliveira M , Sanabria S , Cheeti S , Lin RS , Graham RA , Wilson TR , Parmar H , Hsu JY , Von Hoff DD , Baselga J 
Published: August 2014

Abstract
Background: GDC-0032 is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant cancers. GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that GDC-0032 has enhanced activity against PI3K alpha isoform (PIK3CA) mutant breast cancer cell lines. Preclinical data also show enhanced antitumor activity when GDC-0032 is combined with fulvestrant.
Material and Methods: A Phase 1b dose escalation study was conducted with evaluation of GDC-0032 doses ranging from 6-9 mg QD in combination with fulvestrant 500mg q4wk (with loading dose of 500mg at day 1, 14 and 28) in a modified 3+3 design. A dose expansion cohort was conducted at the recommended Phase 2 dose of 6 mg QD. Safety and tolerability of GDC-0032 was assessed, as well as pharmacokinetics (PK), pharmacodynamic (PD) assessment of PI3K pathway inhibition by paired tumor biopsies and by FDG-PET, and anti-tumor activity by RECIST.
Results: As of 1 Mar 2013, 17 patients were enrolled onto this study with the completion of dose escalation. No dose limiting toxicities (DLTs) were observed at either the 6 mg or 9 mg dose levels. Adverse events (AEs) assessed by the investigator as related to GDC-0032 in ≥10% of patients, were diarrhea, hyperglycemia, stomatitis, fatigue, asthenia, decreased appetite, nausea, mucosal inflammation and rash. No observed apparent PK interactions were observed between GDC-0032 and fulvestrant. The median number of prior systemic therapies was 6. Metabolic partial responses via FDG-PET (≥ 20% decrease in mSUVmax) were observed in 8 out of 11 patients assessed (73%). Confirmed partial responses by RECIST have been observed at both the 6mg and 9mg GDC-0032 dose levels. These include patients who have had prior treatment with fulvestrant. As of 29 May 2013, enrollment onto the dose escalation and expansion cohort has been completed (n = 27). Updated data on safety, pharmacodynamics, efficacy, and biomarker correlates will be presented.
Conclusions: The combination of GDC-0032 and fulvestrant is a well-tolerated regimen with promising preliminary efficacy. GDC-0032 is being further investigated in combination with fulvestrant for patients with hormone receptor-positive advanced breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-3.
Abstract PD3-3: Next generation sequencing shows clonal selection after treatment with anastrozole or fulvestrant in a randomized trial of postmenopausal patients with large operable or locally-advanced hormone-receptor-positive breast cancer
Authors: Iggo RD , Wood HM , Rabbitts P , Quenel-Tueux N , Mauriac L , MacGrogan G , Bonnefoi H ,   HORGEN Investigators
Published: August 2014

Abstract
Background: Unlike chemotherapy, endocrine therapy is not clastogenic or mutagenic, so genetic changes arising during treatment are unlikely to be secondary events provoked by iatrogenic DNA damage. Endocrine therapy for breast cancer is thus a clean setting in which to explore the evolution of tumour genomes under treatment, and the changes seen are likely to be biologically meaningful. To identify such changes we have analysed pre and post treatment biopsies from a clinical trial that compared two endocrine therapies.
Patients and methods: DNA was extracted from pre and post treatment samples from 20 patients enrolled in the HORGEN trial. Postmenopausal patients with large operable or locally-advanced hormone-receptor-positive breast cancer were randomly assigned to receive either neoadjuvant anastrozole or fulvestrant for 6 months in this multicenter randomized phase II study. Low depth next generation sequencing was used to generate DNA copy number profiles for each sample.
Results: The copy number profiles were similar before and after treatment in 10 cases. In three cases new amplicons appeared. In one case the amplicon contained the ESR1 gene, in another the FOXA1 gene, and in the third the NCOA3 gene. In the remaining seven cases where the profiles changed after treatment, the differences affected whole chromosomal arms. In six of these cases the profiles became simpler, indicating that clones with gains and losses of chromosomal arms had been counterselected by the treatment.
Conclusions: Differences between the pre and post treatment biopsies were surprisingly frequent and informative. Genes directly implicated in estrogen signalling were amplified in three cases. This suggests that specific amplicons confer resistance to endocrine therapy. From a clinical perspective, their appearance in a post treatment biopsy probably indicates that the treatment should be changed. A possible explanation for the chromosomal arm changes after treatment, a phenomenon we have dubbed the “wandering arms” phenotype, is that endocrine therapy deprives tumour cells of signals that are necessary for the survival of clones with copy number changes affecting whole chromosomal arms.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-3.