bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of dasatinib in triple-negative breast cancer: results of study CA180059.
Authors: Finn RS , Bengala C , Ibrahim N , Strauss LC , Fairchild J , Sy O , Roche H , Sparano J , Goldstein LJ 
Published: December 2010

Abstract
Abstract #3118
Background: Dasatinib (SprycelR; BMS-354825) is a potent orally-available inhibitor of Src-family kinases and other kinases with anti-proliferative, anti-osteoclastic and anti-metastatic activity demonstrated pre-clinically. Expression profiling suggested that basal-like cancers may be preferentially sensitive to dasatinib. Methods: A Phase II single-agent trial of dasatinib, using a continuous schedule, was performed in patients with advanced triple-negative (as proxy for basal-like) breast cancers. Subjects were required to have measurable locally-advanced or metastatic triple-negative (ER/PR-negative, Her2-normal) disease and prior anthracycline and/or taxane therapy. A 2-stage Gehan design was adopted, with RECIST-defined response as primary endpoint; subjects discontinued for toxicity were considered non-responders. The original dasatinib dose of 100 mg BID (n=21) was reduced to 70 mg BID (n=23) to improve tolerability. Biomarkers were analyzed in tumor and plasma samples obtained for PK analysis. Results: From 12/06 through 12/07, 44 subjects were treated at 14 institutions: median age 55 yrs, median time from diagnosis 30 mo, prior therapy for advanced disease in 29 (66%). Of 43 response-evaluable subjects, 7 discontinued for toxicity prior to on-study assessment. Of 36 subjects with radiographic assessment, there were 2 confirmed PR [1 continues &gt;1 year + 1 discontinued for intolerance at week 16] plus 2 SD lasting &gt;16 weeks. Four additional subjects had transient clinical benefit reflected by improvement in bone pain (anecdotal) or short-term tumor shrinkage (reductions of 11 - 29%). Tolerability was improved at a dose of 70 mg compared with 100 mg BID. In preliminary analysis, fewer subjects experienced any serious adverse event (13% at 70 mg BID vs 48% at 100 mg BID), fewer reported Grade 3 toxicity, including gastrointestinal (10% vs 26%), pleural effusion (4% vs 9%), generalized edema (0% vs 9%) or pericardial effusion (0% vs 9%), and fewer had dasatinib dose reduction (24% vs 61%). Fatigue, myalgia/arthralgia and headache were comparable at the two doses. No Grade 4 drug-related events occurred. Grade 3-4 abnormal laboratory values were uncommon. Biomarker and PK data will be presented. Conclusions: Modest but encouraging single-agent activity was observed with dasatinib in patients with advanced triple-negative breast cancers, with clinical benefit rate of 9.3% (4/43). Future studies are warranted to address optimal dose and schedule of dasatinib in combination with chemotherapy for this challenging tumor type.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3118.
RAD001 (everolimus) in combination with weekly paclitaxel and trastuzumab in patients with HER-2-overexpressing metastatic breast cancer with prior resistance to trastuzumab: a multicenter phase I clinical trial.
Authors: O'Regan R , Andre F , Campone M , Naughton M , Manlius C , Pylvaenaeinen I , Sahmoud T , Hurvitz S 
Published: December 2010

Abstract
Abstract #3119
Background: Resistance to trastuzumab (H) is associated with loss of PTEN and AKT/mTOR activation. Preclinical models demonstrate that RAD001, an oral inhibitor of mTOR (a downstream component of the PI3K/AKT signaling pathway), enhances the efficacy of trastuzumab and suggest that RAD001 could reverse resistance to trastuzumab.&#x2028; Methods: Paclitaxel (T, 80 mg/m2) IV was administered over 60 min on D 1, 8 and 15 q4w. Trastuzumab 4 mg/kg loading dose was administered IV over 90 min on Day 1 (if patient (pt) was not already receiving H), followed by weekly 2 mg/kg IV over 30 min. RAD001 was administered as either a daily (5 and 10 mg) or weekly (30, 50 and 70mg) cohorts. Treatment continues until progression or unacceptable toxicity.&#x2028; Results: As of June 9 2007, 22 heavily pretreated pts were enrolled; 6 to the 5mg daily, 6 to the 10mg daily and 10 to the 30mg weekly cohorts. All pts were resistant to H and all patients, except one, received prior taxane. Median number of prior regimens was 6 (range: 1-26). Two DLTs were observed during the first cycle; febrile neutropenia on the daily 5mg arm and confusional state on the weekly 30mg arm. To date, 17 pts were evaluable for efficacy (Table 1). Among the 7 pts who were resistant to both T and H, 5 had PR (4/5 pts and 1/2 on the 5mg daily and 30mg weekly cohorts, respectively) and 2 had SD &gt;16 weeks. Fifteen pts remain on treatment. The most commonly reported AEs are neutropenia and stomatitis. Recruitment continues.&#x2028; Conclusions: RAD001 is well tolerated in combination with weekly TH regimen. Preliminary efficacy shows a high rate of tumor responses in heavily pre-treated pts, including pts resistant to both T and H. Mature results and biomarkers data will be presented.&#x2028; &#x2028;
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3119.
Did survival of patients with distant metastasis from breast cancer improve during the last three decades? A cohort study on 4071 breast cancers.
Authors: Delozier T , Switsers O , Ollivier J , Levy C , Rivière A , Allouache D 
Published: December 2010

Abstract
Abstract #3129
Introduction: During the last three decades we observed a dramatic improvement in disease free and overall survival in early breast cancer. The improvement of survival of patients who underwent distant metastases is not obvious.&#x2028; The objective of the study was to determine whether the survival of women with distant recurrent breast cancer has improved from 1973 to 2002.&#x2028; Method: We analyzed survival of 4071 women who developed distant metastasis from breast cancer between January 1973 and December 2002 whatever the primary tumor status and initial treatment were. Patients were divided into five groups based on year of breast cancer distant recurrence.&#x2028; Results: In the unadjusted analysis there was a slight but significant improvement in survival across the five groups (p&lt;0.0001), leading to a median survival time of 11.0, 13.9, 17.9, 16.2, 17.3 and 19.8 months respectively and a two-year survival probability of 27.2, 32.3, 39.6, 37.6, 38.7 and 41.0% respectively. In a multivariate analysis including other prognostic factors for metastatic breast carcinoma (age, tumor size, node involvement, tumor grade, estradiol receptors status, site of metastasis and delay from primary treatment), year of recurrence remain a prognostic factor (p=0,001).&#x2028; Survival improvement was more obvious for women with bone metastasis and for women under 70 years old when primary treatment did not include adjuvant chemotherapy.&#x2028; Conclusion: These results suggest that survival of women with distant recurrent breast cancer improved during the last three decades. Nevertheless this improvement is moderate and the long term survival probability is still weak.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3129.
A phase II study of ixabepilone plus trastuzumab for metastatic HER2-positive breast cancer.
Authors: Tolaney SM , Najita J , Chen W , Savoie J , Fornier M , Krop IE , Winer EP , Bunnell C 
Published: December 2010

Abstract
Abstract #3137
Background: The epitholones are a new class of antineoplastic agents which are microtubule inhibitors with low susceptibility to several mechanisms of drug resistance. Ixabepilone (BMS-247550, aza-epothilone B) has demonstrated efficacy as monotherapy or in combination with capecitabine (in anthracycline- and taxane-pretreated metastatic breast cancer) and has recently been approved for use in refractory breast cancer. A multicenter NCI-sponsored study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer.&#x2028; Methods: This phase II nonrandomized study enrolled two cohorts of patients. Cohort 1 received no prior chemotherapy or trastuzumab for metastatic disease and cohort two received one or two prior trastuzumab-containing regimens for metastatic disease. Patients in each cohort received the same treatment regimen of ixabepilone and trastuzumab. Patients received ixabepilone 40 mg/m2 as a 3-hour continuous infusion on day 1 of a 21-day cycle plus trastuzumab once every 21 days. For the initial treatment of trastuzumab, patients received 8 mg/kg IV, and for all subsequent trastuzumab treatments 6 mg/kg. Treatment was continued until disease progression or unacceptable toxicity. Endpoints included response rate (RR), time to progression (TTP), toxicity, and predictive biomarkers.&#x2028; Results: 39 women entered the study (median age 51, range 29-74) with 15 patients in cohort 1 and 24 patients in cohort 2. A median of 7 cycles of therapy were administered in each cohort. In cohort 1, there were 12 partial responses (PR), and 1 patient with stable disease for 5 months (SD). In cohort 2, there were 8 PRs and 9 patients with SD. Across both cohorts, the overall RR was 51%, with a clinical benefit rate (CR + PR + SD for at least 6 months) of 56%. Treatment-related toxicities included neuropathy (grade ≥2, 55%), myalgias (grade ≥2, 20%), anemia (grade ≥2, 18%), neutropenia (grade ≥2, 23%), and elevated transaminases (grade ≥2, 10%). There were no episodes of grade 2 or higher cardiac toxicity. Biomarker data will be presented.&#x2028; Conclusion: This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has an encouraging response rate as first- and subsequent- line therapy for metastatic breast cancer. Clinically significant neuropathy was the major toxicity, and appeared to be cumulative. Based on these results, further evaluation of ixabepilone plus trastuzumab is warranted.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3137.
Lapatinib can restore capecitabine sensitivity in HER2-positive breast cancer.
Authors: Cha Y , Kim H , Han S , Oh D , Kim J , Im S , Bang Y , Kim T 
Published: December 2010

Abstract
Abstract #3157
Background: Lapatinib in combination with capecitabine is an effective treatment option in HER2-positive metastatic breast cancer (MBC) that has progressed after trastuzumab-based therapy. However, the efficacy of lapaptinib plus capecitabine in capacitabine resistant MBC patients and mechanism of sensitivity in these patients is unclear.&#x2028; Methods: In the preclinical part of the study, the effect of lapatinib on 5-FU sensitivity was investigated in a HER2 amplified breast cancer cell line (SKBr3). In the clinical part, MBC patients who progressed after treatments with trastuzumab, anthracycline, and taxane were enrolled in an open-label expanded-access study of lapatinib plus capecitabine (GlaxoSmithKline, USA) at Seoul National University Hospital from Mar 2007 to Apr 2008. Patients received lapatinib (1,250mg/day, 1-21) and capecitabine (2,000mg/m2, D1-14) combination treatment every 3weeks. The clinical data were prospectively collected.&#x2028; Results: In SKBr3 cell line, genes related to 5-FU sensitivity [TS, thymidine kinase 1(TK1), dihydrofolate reductase (DHFR), and ribonucleotide reductase M2 (RRM2)] were downregulated after lapatinib treatment. These genes were more significantly reduced after lapatinib-treatment compared with gefitinib or trastuzumab. In addition, TS reporter gene expression was enhanced by EGFR/HER2. Nuclear translocation of EGFR/HER2 induced by EGF and its association with TS promoter was effectively abolished by lapatinib. In the clinical study, a total of 37 female patients with HER2-positive MBC were analyzed. Sixteen (43%) patients had previously been treated with capecitabine. Overall response rate (RR) was 27.0% (95% CI 12.7-41.3), and disease control rate (DCR) was 83.8% (95% CI 71.9-95.7). During the median follow-up duration of 9.1 months, median progression-free survival (PFS) was 5.6 months (95% CI 4.0-7.2), and median overall survival has not been reached yet. There was no significant difference in RR/DCR and PFS according to prior capecitabine use. Prior capecitabine treatment had been discontinued due to disease progression during treatment in 13 patients. Among these patients with resistance to capecitabine, lapatinib and capecitabine resulted in DCR/PFS comparable to that of patients without exposure to capecitabine. Biomarker analysis of tissue specimen is currently underway and will be presented at the meeting.&#x2028; &#x2028; Conclusion: Lapatinib plus capecitabine demonstrated clinical activity in capecitabine pretreated MBC. Our data suggests that lapatinib may resensitize capecitabine resistant tumors to capecitabine by downregulation of nuclear EGFR/HER2 and TS.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3157.
Cardiac toxicity and adjuvant trastuzumab for breast cancer – the Cancer Centre of Southeastern Ontario experience.
Authors: Flemming JA , Hopman W , Madarnas Y 
Published: December 2010

Abstract
Abstract #3158
Background: In May 2005 several large randomized trials reported a significant improvement in DFS following the addition of trastuzumab (T) to adjuvant chemotherapy (CT) in early stage breast cancer (BC) such that in the summer of 2005 adjuvant T became standard of care for patients (pts) whose tumors over-expressed her2. Cardiotoxicity had been reported as the main toxicity suffered by pts exposed to T. As the generalizability of clinical trial results to the 'real world' is under increasing scrutiny from the oncology community, we undertook this study to identify and follow the population of interest and to characterize cardiac toxicity related to adjuvant T as practice changed.&#x2028; Methods: We conducted a retrospective review of electronic and paper records of all pts prescribed adjuvant T for early stage BC at the Cancer Centre of Southeastern Ontario from June 2005 through January 2007; collecting demographic, disease-related, and treatment-related variables, along with serial left ventricular ejection fraction (LVEF) measurements for each pt.&#x2028; Results: 54 pts prescribed adjuvant T were identified in this time period, nearly half of which were still on T at the time of this analysis. Mean age was 54.4 ± 9.5 years, 38.9% had N0 disease, and 40.7% had left sided tumors, with 42.6% being ER+ and 50% being PR+. Most pts received anthracycline based CT (53.7%) and 39% received an anthracycline/taxane combination. T was concurrently with CT in 14.8% of pts, concurrently with radiotherapy in 33.3% and sequentially in the remainder. T was initiated at a mean of 91.2 days from completion of chemotherapy (range 19-365). Our local protocol mandated LVEF assessments at baseline pre CT, upon completion of CT and/or prior to initiation of T for all pts, and while on T all pts underwent LVEF assessments at 12, 24, 36, 48 and 52 weeks, and in response to any symptoms suggesting cardiac dysfunction. Mean LVEF pre CT and post CT was 64% and 62% respectively. We saw no change in LVEF post CT and pre T. We noted a significant decline in LVEF after 12 weeks on T, from 60.5 ± 6.2% to 56.5 ± 9.5% respectively (p = 0.003), with LVEF values remaining stable thereafter. However, at the time of this analysis only approximately half the pts had completed the full year of therapy. Twelve pts (22.2%) interrupted their T therapy due to a drop in LVEF of &gt;10%, only one pt experienced symptomatic cardiotoxicity requiring treatment. Of these twelve, only two pts restarted T at a later date. Follow-up of those patients still on trastuzumab is ongoing.&#x2028; Discussion: Adjuvant trastuzumab in general clinical practice is associated with significant decreases in LVEF that are associated with premature discontinuation of therapy. A better understanding of factors associated with LVEF decline and the trends in LVEF over time may allow for targeted interventions for pts at risk.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3158.
Neratinib (HKI-272), an irreversible pan erbB receptor tyrosine kinase inhibitor: phase 2 results in patients with advanced HER2+ breast cancer.
Authors: Burstein HJ , Sun Y , Tan AR , Dirix L , Vermette JJ , Powell C , Zacharchuk C , Badwe RA 
Published: December 2010

Abstract
Abstract #37
Background: Neratinib (HKI-272) irreversibly inhibits the tyrosine kinase receptors, erbB1 (EGFR) and erbB2 (HER2). In a phase 1 study, neratinib was tolerable and demonstrated antitumor activity in patients (pts) with solid tumors, including 8 of 25 evaluable pts with erbB2-positive advanced breast cancer. In this open-label, 2-arm phase 2 study, pts with stage IIIB, IIIC or IV erbB2-positive advanced breast cancer were evaluated to further characterize the safety and efficacy of neratinib.&#x2028; Methods: ErbB2 gene amplification in tumor tissue, by FISH was a requirement for study entry. Pts were assigned to arm A if they had prior treatment with trastuzumab and to arm B if they had no prior treatment with trastuzumab or other erbB2-targeted drug. All pts received oral doses of 240 mg of neratinib daily. The primary endpoint was progression-free (PFS) survival rate at 16 weeks (wks).&#x2028; Results: Enrollment of 136 pts (arm A: 66 pts; arm B: 70 pts; median age 50 years [range 31-83 years]) was completed in November 2007. Common neratinib-related adverse events (AEs), any grade, were diarrhea (89%), nausea (29%), vomiting (23%), fatigue (16%), and anorexia (15%). Diarrhea was the only ≥grade 3 AE that occurred in ≥5% of pts, 26/136 (19%) total pts, 27% in arm A and 11% in arm B. Dose reductions occurred in 27% total pts, 36% in arm A and 19% in arm B, most commonly because of diarrhea. The main reasons for discontinuation of the study were disease progression (arm A: 74%, arm B: 43%), and AEs (arm A: 8%, arm B: 4%).&#x2028; 124 pts (arm A: 61 pts, arm B: 63 pts) were evaluable for efficacy based on independent assessment and 131 pts (arm A: 65 pts, arm B: 66 pts) were evaluable based on investigator assessment. The objective response rates (complete or partial response) were 26% (95% CI 16%, 39%) in arm A, 51% (95% CI: 38%, 64%) in arm B for independent assessment and 34% (95% CI: 23%, 47%) in arm A, 62% (95% CI: 49%, 74%) in arm B for investigator assessment. The 16-wk PFS rates were 61% in arm A, 75% in arm B (independent); 57% in arm A, and 78% in arm B (investigator). The median PFS for independent [and investigator assessment] was 23 [22] wks in arm A and 40 [35] wks in arm B.&#x2028; Discussion: Neratinib demonstrates robust antitumor activity in pts with erbB2-positive advanced breast cancer, with objective response rates of 26% in pts who had prior treatment with trastuzumab and 51% in pts who had no prior treatment with trastuzumab. Additional updated efficacy and safety data will be presented.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 37.
Biomarker analysis by tissue microarray technology of Bik, Bcl-2, Bax, ER-α, ER-β, Her2/neu, PCNA, P53, pRB proteins and apoptotic index (by TUNEL) in breast cancer Mexican biopsies.
Authors: Garcia-Hernandez N , Arenas D , Murillo-Ortiz B , Meneses A , Muñoz D , Ruiz-Garcia E , Astudillo-de la Vega H 
Published: December 2010

Abstract
Abstract #4043
Background: &#x2028; The development and progression of epithelial cancers are the results of changes in many genetic networks. Through massive analysis techniques various prognostic factors have been studied to determine proteins implicated in cancer. A new technology used is tissue microarray (TMAs), which allows the assessment of several patients at different stages in a single slide.&#x2028; Methods:&#x2028; TMA blocks with up to 128 cylinders were made by using 1.5-mm diameter tissue cores from each paraffin block. In a series of 70 formalin-fixed carcinomas, we analyzed the immuno-expression of Bik, Bcl-2, Bax, ER-α, ER-β, Her2, PCNA, P53 and RB proteins. For apoptosis detection the TUNEL technique was used. Expression profiles for these tumors were generated with an unsupervised clustering and a T Test analysis.&#x2028; Results:&#x2028; We developed TMAs with samples from Mexican women with breast cancer at different stages (type I, II and III) and compared these with those of non affected breast tissue of the same women's samples. Through a hierarchical cluster we found three subgroups of tumors according to protein expression behavior. The apoptotic process was found in low grade 4.28%; moderate grade 90% and high grade 5.71% of samples. Statistical analysis revealed that Bax gene (p=0.000) expression was significantly increased in samples stage I and underexpressed in samples stage IIIA. The Bcl-2 gene was under-expressed in the majority of samples of the stage II. Even when the Bik gene was detected the protein level was over-expressed in 44.29% of the cases with noa significant correlation with apoptosis (TUNEL) (p=0.006). The samples where there were more alterations of the studied proteins were understood in the stages IIA (T2N0M0) and IIB (T2N1M0).&#x2028; &#x2028; Conclusions:&#x2028; The analysis of specimens of several patients in different stages of the disease turns out to be useful to establish a better diagnosis and prognosis. Differential regulation of these genes, especially Bik and Bax, may contribute to the biological nature of a clinically more aggressive and highly proliferative breast cancers.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4043.