bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-10-07: Risk-Benefit Framework To Evaluate Gene-Expression Profiling in Early Stage Breast Cancer: A Decision Model Developed in Collaboration with Stakeholders
Authors: Roth JA , Veenstra DL 
Published: April 2011

Abstract
Objectives
Recent comparative effectiveness research recommendations have emphasized that stakeholder involvement in research prioritization and design is critical for ultimate acceptance of results. With this recommendation in mind, an interactive risk-benefit model was developed to evaluate gene-expression profiling (GEP) to guide use of adjuvant chemotherapy in early stage breast cancer compared to clinical guidelines. Methods
A stakeholder collaborative feedback process was utilized to develop a decision model to estimate the comparative benefits and harms of GEP relative to NCCN guidelines, including disease recurrences, adverse events, and quality-adjusted life years (QALYs). The model allows users to specify the GEP, node status, patient cohort age, adjuvant chemotherapy relative risk reduction, and patient chemotherapy preferences in each risk stratum. A Markov process was utilized to estimate long-term clinical outcomes. Based on stakeholder concerns about QALY-based outcomes, alternative outcomes such as disease recurrences and adjuvant chemotherapy serious adverse events were presented. The prognostic and predictive properties of the GEPs were derived from published retrospective analyses of RCTs. Adjuvant chemotherapy utility decrements were derived from trial-based adverse event rates. The base case patient was a pre-menopausal woman of age 44. Results
Preliminary analyses indicate that a 2-risk strata GEP, 3-risk strata GEP, and clinical guidelines would identify 50%, 46% and 92% of women to receive adjuvant chemotherapy, respectively. Based on this level of uptake, relative to a scenario where no patients receive adjuvant chemotherapy, these prognostic approaches would prevent 29%, 36% and 34% of distant recurrences, respectively. This scenario results in 17.4 QALYs, 18.1 QALYs, and 17.7 QALYs, respectively. These findings indicate that depending on the specific GEP examined, testing may lead to a net harm or net benefit relative to clinical guidelines, due to variation in risk of disease recurrence, despite avoidance of chemotherapy and side effects in 42% and 46% of women, respectively. Conclusions
GEP to inform adjuvant chemotherapy treatment decisions in early stage breast cancer could lead to an increase or decrease in QALYs relative to the use of clinical guidelines, depending on the specific GEP examined. Stakeholder feedback has indicated that acceptance of model results will likely depend on its degree of transparency, ease of use and interpretation, and ability to present relevant outcome measures. Ongoing efforts are focused on additional collaboration with stakeholders to align model structure and output with current needs.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-10-07.
Abstract P6-11-03: Beyond the Second Line Chemotherapy in Metastatic Breast Cancer: When Stop the Treatment between Science and Conscience
Authors: Bernardo G , Palumbo R , Poggi G , Bernardo A , Teragni C , Frascaroli M , Amatu A , Montagna B , Tagliaferri B , Sottotetti F , Albanese D , Strada MR. 
Published: April 2011

Abstract
Background: Women with metastatic breast cancer (MBC) are increasingly offered third line chemotherapy, but the usefulness of treatment beyond the second line remains a therapeutic challenge. The aim of this study was to determine which benefit could be brought by successive lines of chemotherapy (CT) in patients with MBC and to identify factors affecting outcome and survival.
Patients and methods: This retrospective analysis included 980 women treated with CT for MBC at our Institution over a seven year period (September 1998-September 2006). With overall survival (OS) data updated at December 1, 2008, the median follow-up was 125 months (range 48-192), OS and time to treatment failure (TTF) were calculated according to the Kaplan-Meyer method for each CT line. Cox proportional hazards model was used to identify factors that could influence TTF and OS.
Results: Median OS evaluated from day 1 of each CT line decreased with the line number from 34.8 months (980 patients, first line, range 4-208) to 22.6 months (838 patients, second line), 14.6 months (684 patients, third line), 12.4 months (302 patients, fourth line), 9.4 months (88 patients, fifth line), 8.2 months (45 patients, seven or more lines). Median TTF ranged from 9.2 months to 7.8 and 6.4 months for the first, second and third line, respectively, with no significant decrease observed beyond the third line (median 5.2 months, range 4.8-6.2). In univariate analysis factors positively linked to a longer duration of TTF for each CT line were positive hormonal receptor status, absence of liver metastasis, adjuvant CT exposure, response to CT for the metastatic disease; in the multivariate analysis the duration of TTF for each CT line was the only one factor with significant impact on survival benefit for subsequent treatments (P&lt;0.001).
Conclusions: Our results stress that CT beyond the first line may be beneficial in a significant subset of women treated for MBC. For patients responding to a given CT regimen and asking for further treatment after disease relapse, it appears useful to deliver subsequent active lines to get prolonged TTF and OS benefit. Patients who do not respond to the first two lines of CT should be considered for clinical trials or supportive care.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-03.
Abstract P6-11-09: Pilot Study of Irinotecan and S-1 for Advanced and Metastatic Breast Cancer
Authors: Tanaka M , Furusawa H , Kamada Y , Sagara Y , Anan K , Miyara K , Kai Y , Wakamatsu S , Uga T , Tamura K , Mitsuyama S 
Published: April 2011

Abstract
Patients with metastatic breast cancer (MBC) are often treated with multiple regimens, and viable options may soon be exhausted. Irinotecan (CPT-11), a topoisomerase 1 inhibitor, is rarely used in this setting, however. Approved for advanced breast cancer in Japan, S-1 is a pyrimidine derivative comprising the combination of tegafur, gimeracil and oteracil. Irinotecan is combined with S-1 (IRIS) to obtain an additive effect, even in the presence of high thymidylate synthase in breast cancer cells. This combination has also been successfully used for gastro-intestinal malignancies in Japan. Method: This study was divided into two steps: step 1, in which the safety profile of the regimen was determined; and step 2, in which tumor response was evaluated if the safety profile was considered acceptable. Irinotecan was given intravenously at a dose of 80 mg/m2 on days 1 and 8 and S-1 orally at 80-120 mg/day depending on body surface area for 2 weeks. The cycle was repeated every 3 weeks.
Results: A total of 21 patients were registered in the study. Median age was 50 years (range, 26 -69 years). Performance status was 0 and 1 in 20 and 1 patients, respectively. Six patients were enrolled in step 1. Grade (G) 3 fatigue and vomiting were observed in 1 patients, G 3-4 neutropenia in 4 and G 3 anemia in 1. The toxicity profile in step 1 was determined acceptable to move on to step 2. Step 2 included 15 patients treated with IRIS. Grade 3-4 neutropenia occurred in 7 out of these 15 patients, fatigue in 1, diarrhea in 3 and anorexia in 1. All patients had previously received anthracyclines and taxanes. Eighteen patients, including 3 patients in step 1, were evaluable for response. A partial response was obtained in 5 patients (27.8%), including in 1 patient who had a history of 4 previous treatments. Progression-free survival in these patients was 137+, 147, 168+, 304+ and 364+ days; no progressive disease was observed in 4 of them. In addition, stable disease was obtained in 5 patients (27.8%) in whom 2 patients experienced SD for longer than 6 months. Conclusion: These results indicate that the IRIS regimen has an acceptable safety profile and modest activity against breast cancer in patients who have been heavily treated with chemotherapy for MBC. We believe the patients responded to the IRIS regimen because irinotecan has a different mechanism of action as compared to other drugs commonly used for breast cancer and complete cross-resistance may not exist between S-1 and capecitabine. This regimen is commonly used for gastric or colorectal cancer in Japan and is considered to be highly tolerable. Therefore, we conclude that this regimen has potential as an option to treat advanced and metastatic breast cancer, although attention must be paid to diarrhea, the dose-limiting toxicity of irinotecan and S-1.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-09.
Abstract P6-11-13: Phase I Study of Combined S-1 Plus Weekly Paclitaxel Therapy in Patients with Metastatic Breast Cancer
Authors: Watanabe J , Takahashi K , Tanaka K , Tadokoro Y , Ogiya A , Uematsu T , Kimura M. 
Published: April 2011

Abstract
Introduction: S-1, a novel anticancer compound, contains tegafur, a prodrug of fluorouracil (FU), 5-chloro-2.4-dihydroxypyridine, which prevents FU degradation, and potassium oxonate, which prevents drug-induced diarrhea, has a broad spectrum of activity against gastric, colorectal, head & neck, and breast cancers. While combined S-1 with cisplatin or paclitaxel (PAC) therapy is feasible and highly active against gastrointestinal cancer, the feasibility in breast cancer patients has not yet been clarified. We conducted a phase I study of combined S-1 plus weekly PAC therapy (S-1/PAC) to determine the maximum tolerated dose (MTD), recommended dose (RD) and dose-limiting toxicities (DLT) in patients (pts) with HER2-negative, taxane-naïve metastatic breast cancer (MBC).
Methods: S-1 was administered orally from day 1 through day 14 and PAC was administered intravenously on days 1, 8 and 15 of each 28-day cycle. Since S-1 is prescribed at the dose of 80mg/m2 in monotherapy, the primary dose levels (level 1) were set at 65 and 70mg/m2, respectively. The final dose (level 3) was set at 80mg/m2 for each drugs. DLT was defined over 2 cycles.
Results: Ten MBC pts were enrolled in the study. No DLTs were documented. Although grade 1 or 2 adverse events were seen in all pts, no cases of febrile neutropenia or Gr 4 neutropenia were observed. Of the 8 evaluable pts, 3 pts achieved partial response and 4 pts had stable disease.
Conclusion: Based on the results of this study, RD was determined to be 80mg/m2 for either drugs. We conclude that S-1/PAC was well-tolerated and highly active against HER2-negative MBC.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-13.
Abstract P6-12-05: Ways To Understand Mechanism of Action for Targeted Drugs? Gene Expression Analyses from Paired Biopsies in Patients with Advanced Breast Cancer in a Substudy from the Randomized Study Docetaxel +/− Sunitinib A6181064
Authors: Lindstrom LS , Giorgetti C , Smeds J , Borg A-L , Liljegren A-L , Skoog L , Kern KA , Bergh J. 
Published: April 2011

Abstract
Background: The randomized SUN 1064 study, docetaxel +/− sunitinib included 593 patients with advanced breast cancer. The response rate was statistically significantly (p-value=0.001) higher in the combined arm, but no difference in progression free survival or overall survival was found, median 24.8months in combined arm and median 25.5 months in docetaxel arm (HR 1.21: 95% confidence interval 0.91-1.60).
This substudy aimed at unraveling gene expression patterns together with differentially expressed genes, contrasting gene expression before and after docetaxel +/− sunitinib treatment. The study also aimed at testing if sunitinib altered the gene expression of previously proposed sunitinib receptor tyrosine kinase targets. Material and methods:
In a substudy at Karolinska we aimed to have cytological biopsies taken; before start of therapy and repeated in both arms after 14 (+/−1 day) days of therapy, randomly consisting of either docetaxel at 100 mg/m2 q 3 w, or docetaxel 75 mg/m2 q 3w + sunitinib 37.5 mg orally day 2-15. Eighteen of 21 patients accepted participation. From 14 (7 per arm) individuals we had sufficient material to make paired comparisons. We used the HG-U133plus2 Affymetrix chip containing 54 675 probe sets in the 14 paired pre-treatment and post-treatment patient samples.
Results:
Unsupervised hierarchical clustering revealed differential gene expression patterns for the combined arm (Figure A) compared with docetaxel alone (Figure B).
The sunitinib proposed target receptor tyrosine kinases, showed no clustering patterns associated with the combined sunitinib and docetaxel treatment. The top 100 differentially expressed genes did not include the proposed sunitinib target genes. However interestingly, genes involved in the VEGF signaling pathway and apoptosis were significantly more frequently upregulated and those involved in the cell cycle were more frequently down-regulated in patients after treatment of sunitinib and docetaxel in combination, in contrast to the pre-therapy situation.
Conclusions:
Unsupervised hierarchical clustering revealed differential gene expression patterns corresponding to before and after combined sunitinib and docetaxel treatment, clearly clustering patients into the two groups. Interestingly, genes involved in the VEGF signaling pathway, apoptosis and cell cycle were modulated significantly more frequently by combined therapy treatment.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-12-05.
Abstract P6-12-06: Oral Vinorelbine and Capecitabine Plus Bevacizumab in Recurrent Inflammatory Breast Cancer: Gene Profiling and Response to Treatment
Authors: Fumagalli L , Curigliano G , Locatelli M , Bagnardi V , Bertolini F , Mancuso P , Giudici S , Goldhirsch A. 
Published: April 2011

Abstract
Background: Therapies that target vasculolymphatic processes - angiogenesis, lymphangiogenesis, and vasculogenesis — have shown potential in the treatment of inflammatory breast cancer.
Methods: We randomly assigned 46 patients to receive oral vinorelbine 55 mg per square meter of body surface on days 1 and 3 and capecitabine 2000 mg per square meter on days 1 to 14 every 3 weeks either concurrent or sequential to bevacizumab 15 mg per kilogram of body weight on days 1 and 21 (BEVIX). The primary end point was progression-free survival;
the response rate and overall survival were a secondary end point. For correlative studies we collected baseline tissue and blood samples of all patients. Gene expression profiling was performed using Affymetrix HG-U133 Plus 2.0 arrays. Data were analyzed using Partek Genomic Suite 6.4 and GeneSpring 7.0. Tissue from normal breast was used as control.
Results: From July 2007 through January 2010, a total of 46 patients were enrolled. Concurrent oral vinorelbine and capecitabine plus bevacizumab significantly increased the objective response rate as compared to the sequential treatment (11.1% vs. 46.4%, p=0.025). No difference in progression-free survival was observed between the two arms (median time to progression 4.3 vs. 4.7 months, p=0.69; Hazard Ratio: 0.86, 95% CI: 0.41-1.80). The median overall survival was 9.1 months in concurrent arm and 15.8 months in sequential arm, (p=0.43). Global gene expression was analyzed in tumor samples from 18 pts bearing a triple negative phenotype. This cohort displayed a specific gene expression profile, including high expression levels of several cytokeratins, Aurora kinase A, Cyclin E and others, similar to the basal-like subtype. This profile did not include genes previously reported as differentially expressed in inflammatory breast cancers. We identified a set of 75 genes whose expression correlates with response to bevacizumab base therapy.
Conclusions: BEVIX is an active treatment for patients with recurrent inflammatory breast cancer. These tumors showed a gene expression pattern similar to that of basal-like type. We identified a set of 75 genes whose expression levels predict the response to BEVIX. The validity of this expression signature is currently being assessed. Supported by Roche and Associazione Italiana per la Ricerca sul Cancro (AIRC) grants. Data partially submitted to 2010 ASCO Meeting
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-12-06.
Abstract P6-12-07: Phase II Trial of Vinorelbine and Sorafenib in Metastatic Breast Cancer (MBC)
Authors: Luu T , Frankel P , Chung C , Mortimer J , Hurria A , Somlo G. 
Published: April 2011

Abstract
BACKGROUND
Vinorelbine, a semisynthetic vinca alkaloid, at 20-25mg/m2 has a response rate of 15-30% for second line therapy of MBC. Sorafenib is an oral multi-kinase inhibitor against the tyrosine kinases for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), Flt-3 and c-Kit receptors. In preclinical studies, sorafenib demonstrated anti-tumor activity by inducing complete tumor stasis in a variety of tumor types through the Raf/MEK/ERK pathway. In the NCI H460 cell line for NSCLC tumor xenograft, synergy between vinorelbine and sorafenib were observed. We established the phase II recommended dose in MBC for the combination of vinorelbine (d1,18,15 on a 28 day cycle) with daily sorafenib at vinorelbine 20mg/m2 and sorafenib 200mg oral twice daily (reported at ASCO 2010). Phase II trial will complete in 6/2010. METHODS
Eligibility include: MBC with adequate end-organ function and performance status 0-2 who have up to two lines of prior chemotherapy regimens. Patients were treated at the recommended phase II dose as above. Tumor response was evaluated every two cycles by RECIST criteria. N=39 (target accrual 41 by 6/10) patients enrolled at the above recommended dose from 6/09 to 6/10. Treatment was continued until disease progression or unacceptable toxicity. RESULTS
Sites of metastatic disease included liver, lung, bone, bone marrow and skin. A total of 22/39 patients were enrolled prior to 2/17/2010 and are therefore evaluable for 4-month progression free survival (PFS) evaluation at this time. Median age of these patients was 56 yrs (range 39-72). ECOG performance status is 0 in 8 and 1 in 14 participating patients. Prior number of chemo regimens for MBC was 0 (n=4), 1 (n=10), and 2 (n=8). There was 1 partial response (PR) with 2 prior, and 8 stable disease (SD) with PFS for more than 4 months with 6 with 1 prior and 2 with 2 prior regimens for MBC. A total clinical benefit rate (PR+ SD) of 9/22 (41 %). SD patients included 1 who progressed at 11 months (1 prior), and 3 still on therapy.
The patient with SD for 11 months previously progressed in 2 months on abraxane. Toxicities resulted in treatment discontinuation in only 2 patients. Toxicities include: Grade 3 hand-foot reaction (n=3), Gr 4 ANC (n=3), Gr 3 fatigue (n==3), Gr 3 Diarrhea (n=2), Gr 3 hypertension (n=2), Gr 3 infection (n=3), 2 skin), Gr 3 elevated lipase (n= 1), Gr 3 hypophosphatemia (n=2), Gr 3 hyponatremia (n=2), Gr 3 Somnolence (n=1), Gr 4 PLT (n=1), Gr 3 back pain (n=1), and Gr 3 cough (n=1). CONCLUSIONS
The addition of sorafenib to vinorelbine to date showed a promising 41% clinical benefit rate in this heavily pretreated MBC population with a tolerable toxicity profile. Follow-up is continuing, we will report on the entire cohort of 41 patients at SABCS.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-12-07.
Abstract P6-12-09: A Phase I-II Trial of Dasatinib (D) in Combination with Weekly (w) Paclitaxel (P) for Patients (Pts) with Metastatic Breast Carcinoma (MBC)
Authors: Morris PG , Abbruzzi A , D'Andrea G , Gilewski T , Lake D , Bromberg J , Dang C , Dickler M , Modi S , Seidman AD , Sklarin N , Chang J , Patil S , Norton L , Hudis CA , Fornier MN. 
Published: April 2011

Abstract
Background: Inhibition of SRC is a novel approach for MBC. D is an inhibitor of multiple tyrosine kinases, including the SRC family. Pre-clinical data show D inhibits multiple breast cancer cell lines, including those of “basal-like” subtype. In preclinical models D + P had superior antitumor activity to either agent alone. We designed this phase I-II study to translate this observation.
Methods: For phase I: pts with MBC, ECOG PS 0-1, normal hepatic, renal, marrow function were eligible. Pts with pleural/pericardial effusions were excluded. For phase II: pts had measurable, HER2-negative MBC, ≥2 prior rx for MBC. Prior taxanes, stable brain metastases and baseline neuropathy grade ≥1 were allowed. Cycle (C) consisted of wP 80 mg/m2 IV 3/4 weeks + D 70mg orally daily; escalating to 100 mg, 120 mg and 150 mg in cohorts of 3pts. Toxicity was assessed by CTCAE v3.0, response by RECIST.
Results: 17 pts enrolled (15 phase I; 2 phase II); median age 54 (range 35-74), median PS=1 (range 0-1). 12 (71%) pts rcvd prior adjuvant chemoRx. Pts rcvd a median of 3 prior rx for MBC (range 0-12). Pts rcvd median of 2 C of D + P (range 1-14). One DLT occurred at 150mg (G3 fatigue); this cohort was expanded with no further DLTs. However 3 pts on this dose level withdrew;1 pt delayed hypersensitivity rash (grade 1), 1 pt febrile neutropenia (grade 3), 1 pt paclitaxel pneumonitis (grade 3). Therefore the phase II dose is D 120mg. Overall the most common toxicities have been hematologic and low G (table). 13 pts are assessable for response; 4 patients (31%) had a PR, including 3 patients previously treated with taxanes. 5 pts (29%) had stable disease.
Toxicities &gt; Grade 1
Conclusion: Treatment with wP and D is feasible in pts with MBC. In the phase I study, 1 DLT occurred at D 150mg but due to cumulative toxicities the recommended dose for the ongoing phase II study is 120mg. Preliminary evidence of activity has been seen in taxane-pretreated pts at the phase II dose. Identification of biomarkers to select appropriate pts for this therapeutic approach is the subject of ongoing correlative studies.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-12-09.