bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-14-07: A Phase 1 Study To Assess the Safety, Tolerability and PK of ARRY-380 — An Oral HER2 Inhibitor
Authors: Moulder SL , Baetz T , D ‘Aloisio S , Fernetich G , Sajan B , Freeman B , Barrett E , Guthrie KM , Kass CL , Chia SKL. MD 
Published: April 2011

Abstract
Background: ARRY-380 is a potent, orally active small molecule that selectively inhibits HER2 signaling in vitro and in vivo. Methods: Patients (pts) with HER2+ MBC or other tumor types with published evidence of HER2 expression were treated with ARRY-380 as a single oral dose on C1 D1 followed by continuous dosing on C1 D3, in a BID schedule. Dose escalation was performed using standard DLT rules after all pts within a cohort completed the first cycle. Serial PK assessments were performed on D 1, 2, 3 and on D 15 of C1. Preliminary Results: As of 1 June, 2010, 30 pts have been treated at doses ranging from 25 mg to 800 mg BID. Pts had a median age of 57 years (range: 31-77 years). Cancer types included HER2+ MBC (n=23), CRC (n=6), and salivary gland (n=1). All HER2+ MBC pts had received prior trastuzumab and most (78%) had received prior lapatinib. The MTD (600 mg BID) has been determined in the dose escalation study. ARRY-380 was generally well-tolerated. One DLT of reversible grade 3 AST and one DLT of reversible grade 3 AST/ALT were noted at the 800 mg BID dose level. Other related AEs have been predominantly mild and include Grade 1 nausea, rash, and fatigue and Grade 2 fatigue. No treatment-related cardiac events have been reported. PK analyses indicate a trend for increasing Cmax and AUC with increasing dose, a median Tmax of 2 hours, and a mean t1/2 of 5.3 hours across doses. Of the 15 HER2+ MBC pts evaluable for response at doses ≥200 mg BID, 1 (7%) pt had a confirmed PR and 8 (53%) had SD accompanied by regression of tumor lesions. Of the 8 pts with SD, 5 pts demonstrated SD for ≥4 months. The rate of PR + SD ≥4 months was 43%. The HER2+ MBC pt with a PR had complete regression of all target and non-target lesions and a change in CEA from 71.1 to 3.5 ng/mL [NR = 0.0-3.0 ng/mL]. This pt is currently in Cycle 5 and has received 6 prior lines of therapy for advanced disease with a best response of PD on lapatinib. Conclusions: ARRY-380 has demonstrated a generally well-tolerated safety profile with a low incidence and severity of rash and diarrhea. ARRY-380 has shown promising signs of antitumor activity in a heavily pretreated HER2+ MBC population (43% of pts with PR or SD ≥4 months). These safety and preliminary efficacy data compare favorably to historical data of other HER2-targeted agents.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-07.
Abstract P3-14-14: Activation of SRC and MAPK Mediates Resistance to Lapatinib in ER-/ERBB2+ Breast Cancer
Authors: Jegg A-M , Ward T , Iorns E , Gallas M , Pegram M. 
Published: April 2011

Abstract
Background
Resistance to lapatinib represents a significant problem in the treatment of ERBB2+ breast cancer, especially after failure of prior trastuzumab therapy. A number of resistance mechanisms have been identified in recent years that limit the anti-tumor effects of lapatinib. These mechanisms include the activation of ERα signaling, and sustained activation of AKT either through coexpression of receptor tyrosine kinases (IGF-IR, AXL, MET, ERBB3), loss of PTEN or activating mutations in PIK3CA. However, these mechanisms have been shown to confer resistance primarily in ER+/ERBB2+ breast cancer cells; the mechanisms of resistance to lapatinib in ER-/ERBB2+ breast cancer (∼ 50% of ERBB2+ breast cancers) remain poorly understood.
We hypothesized that resistance to lapatinib in ER-/ERBB2+ breast cancer cells can be mediated by activation of alternative signaling pathways which bypass the PI3K/AKT signaling axis. Materials and Methods
To investigate the mechanisms of acquired resistance to lapatinib we generated ER-/ERBB2+ and ER+/ERBB2+ breast cancer cells resistant to lapatinib at the clinically relevant concentration of 2.6 uM (SK-lapR and BT-lapR). Resistance to lapatinib was achieved by exposure of SKBR3 and BT474 cells to increasing concentrations of the drug, and resistant cells were selected through serial passage. The activation status of multiple signaling pathways in lapatinib sensitive and resistant cells was determined by western blot analysis, and the role of individual signaling pathways in promoting resistance to lapatinib was investigated in cell proliferation assays using selective small molecule inhibitors. Results and Discussion
Consistent with previous studies, we show that inhibition of ERα signaling using 100 nM fulvestrant in combination with lapatinib restored lapatinib sensitivity and effectively leads to growth arrest and cell death in ER+/ERBB2+ BT-lapR cells (P&lt;0.001). However, none of the previously proposed mechanisms of resistance to lapatinib were apparent in our SK-lapR cells (ER-/ERBB2+). Strikingly, these cells which are stably resistant to lapatinib show no activation of AKT even in the absence of lapatinib. Rather, they exhibit increased phosphorylation of SRC kinase (3.9 fold, analyzed with ImageJ) and no inhibition of ERK1/2 after treatment with lapatinib compared to sensitive SKBR3 cells. Inhibition of SRC activity with 1uM AZD0530 in combination with lapatinib significantly reduced growth of SK-lapR cells compared to treatment with lapatinib alone (P&lt;0.05). These data reveal potential novel mechanisms for lapatinib resistance in ER-/ERBB2+ breast cancer, and may indicate therapeutic strategies to prevent or overcome lapatinib resistance.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-14.
Abstract P3-14-15: Lapatinib Plus Capecitabine in Trastuzumab Pre-Treated HER2- Positive Metastatic Breast Cancer: The Canadian Lapatinib Expanded Access Program Experience
Authors: Chang J , Chia S , Prady C , Haider K , Grenier D , Lopez P , Ghedira S. 
Published: April 2011

Abstract
BACKGROUND:
The global lapatinib expanded access programme (LEAP) provided access to lapatinib (L) combined with capecitabine (C) for women with HER2- positive metastatic breast cancer (MBC) who were previously treated with an anthracycline (A), taxane (T) and trastuzumab (TRAS) in 45 countries. The eligibility criteria and the dose of given drugs resembled that used in the phase III clinical trial EGF 100151, with the exception that patients (pts)previously exposed to C and pts with an ECOG performance status of 2 could be included as well. L is a dual tyrosine kinase inhibitor of EGFR and HER2. L plus C is an effective treatment option in T-refractory HER2-positive MBC. 148 Canadian pts were enrolled. METHODS:
LEAP enrolled patients with ErbB2-positive, locally advanced and MBC showing progressive disease following prior therapies with A, T, TRAS-containing regimens. Pts received L (1,250 mg/day) and C (2,000 mg/m2/day, days 1-14, every 21 days). We analyzed 148 Canadian LEAP pts recruited from seven centres for demographics, duration of therapy, L compliance, left ventricular function, progression-free survival (PFS), and overall survival (OS). RESULTS:
Data cut off for these analyses was Jan 10, 2010. [Data were not available for all 148 pts. The median age was 52 y (range 29-80 y) for 147 pts (145 women, 2 men). Ninety-five pts (64.6%) had no prior C and 52 (35.4%) had prior C (n=147). Study medication was discontinued for 142 pts (96.6%): 110 (74.8%) for progressive disease; 17 (11.6%) for adverse events; 8 (5.4%) for patient preference; and 3 (2%) were transitioned to the commercial supply of L. The median duration of therapy was 18.95 wk, ranging 0.1 to 96 wk (n=137). L compliance data showed that 73.7% of pts received ≥80% of the L dose (n=122). Median baseline left ventricular function (LVF) was 60%, ranging 50% to 81% (n=142). The median LVF at study end was 61%, ranging 37% to 83% (n = = 96). There was an amendment in June 2008 to end the collection of disease progression and/or death dates. Median PFS and OS were 22.1 wk (95% CI: 18.9-26.7), and 48 wk (95% CI: 42.3-…), respectively (n=71). CONCLUSIONS:
L combined with C is an effective option for women with refractory HER2-positive MBC. The results seen in the Canadian subset enrolled in LEAP were similar to the results of EGF 100151 and the Global LEAP in the efficacy and safety data.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-15.
Abstract P3-14-16: Can Resistance to Trastuzumab Be Reversed by Endocrine Therapy? Results from a Proof-of-Principle Trial in Postmenopausal Patients with Hormonal Receptor (HR) Positive, HER-2 Positive Advanced Breast Cancer (SAKK 23/03)
Authors: Koeberle D , Ruhstaller T , Jost L , Pagani O , Zaman K , von Moos R , Crowe S , Thuerlimann B 
Published: April 2011

Abstract
Introduction: Trastuzumab (T) is a cornerstone in the treatment of patients with HER2-overexpressing advanced breast cancer and development of resistance to T is a major therapeutic problem. HER-2 is part of a highly interactive signaling network that may impair efficacy of endocrine therapy. A sequential treatment design was chosen in this trial to ensure complete resistance to single agent therapy before receiving both a non-steroidal aromatase inhibitor (AI) and T. Any kind of clinical activity with combined treatment of AI and T after progression of single agent treatments could indicate restoration of sensitivity as a consequence of cross-talking and networking between both pathways.
Methods: Key eligibility criteria included postmenopausal patients (pts.) with advanced, measurable, HER-2 positive (assessed by FISH, ratio (≥2)), HR positive disease and progression on prior treatment with a non-steroidal AI, e.g. letrozole or anastrozole, either in an adjuvant or advanced setting. Pts. received standard dose T monotherapy either weekly or three-weekly in step 1 and upon disease progression, continued T in combination with letrozole in step 2. The primary endpoint was clinical benefit response (CBR: CR, PR or SD for at least 24 weeks (+/− 1 week) according to RECIST) in step 2.
Results: Thirteen pts. were enrolled in five centers in Switzerland. In step 1, six pts. (46%) achieved CBR. Median time to progression (TTP) was 161 days (Range: 50 - 627). Based on data collected until the end of May 2010, CBR was observed in seven out of the eleven evaluable pts. (64%) in step 2, including one pt. with partial response. Four of the seven pts. within step 2 that achieved CBR also had CBR in step 1. Seven out of eleven pts. have documented tumor progression during step 2 treatment. Median TTP for all eleven pts. was 184 days (range 61 - 471). Mean time on study treatment (TTP in step 1 plus TTP in step 2) for pts. reaching step 2 was 380 days (range 174 - 864). Adverse events were generally mild. Conclusion: Results of this proof-of-principle trial suggest that complete resistance to both AI and T can be overcome in a proportion of pts. by combined treatment of AI and T, as all pts. served as their own control. Our results appear promising for a new treatment strategy which offers a chemotherapy-free and well-tolerated option for at least a subset of the pts. with HR positive, HER-2 positive breast cancer. Further trials will need to corroborate this finding.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-16.
Abstract P3-14-18: Result of Phase I Part of a Phase I/II Study of Lapatinib (L) Plus Oral Vinorelbine (oVNR) in Metastatic Breast Cancer (MBC) Patients Overexpressing ErbB2
Authors: Lu Y-S , Lin C-H , Shen Y-C , Lan CY , Cheng A-L , Huang C-S. 
Published: April 2011

Abstract
Background: Lapatinib(L) is effective in overexpressing ErbB2 MBC patients. Oral vinorelbine (oVNR) has similar efficacy to that of the injection formulation and has demonstrated generally favorable tolerability. Oral medications provide convenient treatment and satisfactory life quality. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies.
Methods: This open-label, single-center, single-arm phase I study aimed to determine the maximum tolerated dose (MTD) and recommended dose of L+oVNR to women with ErbB2+ MBC, in progression after trastuzumab-taxane based treatment. Patients refractory to any line of anticancer treatment including vinorelbin was allowed to join in this study, except lapatinib. Cohorts of 3 patients received oral vinorelbine at escalating doses of 30-80 mg/day on day 1 and day 8 every 3 weeks (q3w) combined with lapatinib at escalating doses of 1000-1250 mg/day given po continuously, with each successive cohort until the MTD (2/3, 2/6 patients experiencing dose-limiting toxicity [DLT]) was reached. Additional patients received repeated administration at the recommended dose. G-CSF as primary prophylaxis of febrile neutropenia was not permitted.
Results: 15 patients have been enrolled. During dose escalation, 2 of 3 experienced DLT at dose level of oral vinorelbine 60mg/kg day 1 and day 8 q3w plus lapatinib 1000mg/day. One with grade 3 diarrhea and the other with prolonged grade 3 neutropenia. This dose level was declared as MTD. Therefore we stop recruiting patient into next dose level of oral vinorelbine 60mg/kg plus lapatinib 1250mg/day. Recommended dose was lapatinib 1000mg/day with oral vinorelbine 50mg/kg day 1, day 8 q3w. There is no DLT experienced in 12 patients with the dose level below MTD. The most frequent treatment-related adverse events included diarrhea, skin rash, and fatigue, mostly grade 1-2. As of June 2010, 6 patients are still on treatment. Efficacy signals in other 9 patients included 2 maintained stable disease (SD) &gt; 6 months (both of them had unconfirmed PR during treatment), 1 unconfirmed partial response (PR), 1 SD &lt; 6 months, and 4 progressive disease (3 of them had refractory to vinorelbine before). Phase II study with the recommended dose was just starting. Final result of the efficacy signal in phase I part and the toxicity profile of more patients receiving recommended dose will be presented at the meeting.
Conclusions: The combination of lapatinib and oral vinorelbine is tolerable and has antitumor activity in heavily pretreated ErbB2+ MBC. Further phase II study is underway.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-18.
Abstract P3-15-01: Primary G-CSF Prophylaxis during the First Two Cycles Only or Throughout All Chemotherapy Cycles in Breast Cancer Patients at Risk of Febrile Neutropenia: Final Results from a Phase III Trial of the Dutch Breast Cancer Trialists Group (BOOG)
Authors: Aarts MJB , Peters FPJ , Dercksen WMW , Mandigers CMPW , Stouthard J , Nortier HWR , Kamm YJL , van Warmerdam LJC , van der Rijt CCD , van Gastel S , Joore M , Kessels A , Tjan-Heijnen VCG. 
Published: April 2011

Abstract
Background: In patients at risk of febrile neutropenia (FN), the highest incidence of FN is seen during the first chemotherapy cycles. This observation questions the effectiveness of continued G-CSF prophylaxis during later chemotherapy cycles.
Methods: We conducted a multicenter phase III study in breast cancer. Patients were randomized to primary G-CSF prophylaxis during the first two chemotherapy cycles only (experimental arm) or to primary G-CSF prophylaxis throughout all chemotherapy cycles (standard arm). Patients were eligible if treated with 3-weekly chemotherapy, being at risk of FN according to criteria of international guidelines. This was an equivalence study, aimed to include 230 patients, with FN as primary endpoint. Results: An independent Data Safety Monitoring Board recommended premature closure of the study because of an unacceptable increase in FN rate in the experimental arm. In total, 85 patients enrolled the experimental arm and 84 patients the standard arm till 15 th December 2009. Baseline characteristics were well belanced: age ≥65years in 93% versus 95%, ECOG PS of zero in 82% versus 88%, treated with docetaxel containing chemotherapy in (neo)-adjuvant setting in 97% versus 100%, respectively. At least one episode of FN was seen in 27 (32%) patients of the experimental arm compared with 4 (5%) patients in the standard arm (P&lt;0.0001). Notably, in the experimental arm FN occurred predominantly in the third cycle, whereas in the standard arm FN was seen throughout all cycles. Fever, infection and/or mucositis led to serious adverse events in 31 (36%) patients in the experimental arm versus in 11 (13%) patients in the standard arm (P&lt;0.001). In both arms, 5% of patients stopped or changed treatment because of toxicity. Most patients experienced only one FN episode. In these, chemotherapy was mostly given as planned, but in 61 % of patients with secondary G-CSF prophylaxis and in 21% of patients with secondary antibiotic prophylaxis (in the experimental arm). Conclusion: We conclude that in patients at risk of FN, primary G-CSF prophylaxis cannot be limited to the first chemotherapy cycles, despite the well known increased FN incidence in the first cycles without prophylaxis. With only 2 cycles protected, FN risk is increased in the third cycle. Support: The Netherlands organization for health research and development (ZonMw) and sanofi-aventis Netherlands B.V.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-15-01.
Abstract P3-15-03: Prospective Evaluation of the Drug-Metabolizing Enzyme Polymorphisms and Toxicity Profile of Docetaxel in Korean Patients with Early-Stage Breast Cancer Receiving Adjuvant Chemotherapy
Authors: Kim K-p , Ahn J-H , Jung K-H , Kim S-B , Lim H-S. 
Published: April 2011

Abstract
Background
Interindividual variability of pharmacokinetics may account for unpredictable toxicity of docetaxel. Pharmacogenetic analysis on the metabolic pathway of docetaxel has been performed in hopes of identifying predicting factors related to docetaxel-related toxicities. Methods
From March 2007 to June 2008, female patients with early-stage breast cancer receiving docetaxel-containing adjuvant chemotherapy were included in this study. The 4 cycles of planned dose of docetaxel (100 mg/m2) was performed as adjuvant chemotherapy, following 4 cycles of adriamycin and cyclophosphamide. We evaluated toxicity profile of docetaxel according to the drug-metabolizing enzyme or transporter polymorphisms reported to affect the pharmacokinetics of docetaxel. The single nucleotide polymorphisms (SNPs) of CYP3A5 gene (6986 A&gt;G), ABCB1 gene (1236 C&gt;T, 3435 C&gt;T, 2677 G&gt;T(A)), ABCC2 gene (-24C&gt;T, 1249 G&gt;A, 3972 C&gt;T, rs1276549) and SCLO1B3 gene (334 T&gt;G, 699 G&gt;A, rs11045585) were sequenced from individuals. Toxicities including neutropenia was evaluated for the 1st cycle of docetaxel and defined according to the NCI CTCAE version 3.0. Results
Pharmacogenetic analysis was performed in 218 Korean women who had received the planned chemotherapy. With regard to ABCB1 3435 C&gt;T, ABCB1 3435 T/T had significantly higher risks of neutropenia (P=0.015). Meanwhile, allele frequencies for CYP3A5 6986 G and ABCB1 3435 T revealed a trend for neutropenia (P=0.107 and 0.068). We could not find any other association between genotypes and other toxicities. Discussion
Although ABCB1 3435 T/T was significantly associated with docetaxel-related neutropenia in our study population, polymorphism of pharmacogenetic genes related to docetaxel metabolism did not appear to be evidently associated with docetaxel-related adverse events. Further external validation of these genes may be required to allow them to enter clinical practice.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-15-03.
Abstract P3-15-04: The Clinical Course of Metastatic Breast Cancer Patients with a Congestive Heart Failure after an Epirubicin-Based Treatment
Authors: Ryberg M , Nielsen DL , Jensen MT , Nielsen G , Andersen PK. 
Published: April 2011

Abstract
Background. Patients treated with epirubicin are at risk for the development of congestive heart failure (CHF). However, only limited data are available, which is describing the outcome for these patients. Materials and methods. The patients were recruited consecutively from 1,097 anthracycline-naïve patients with metastatic breast cancer, who were admitted to Herlev Hospital from November 1983 - November 2003 for an epirubicin-based chemotherapy. No patients had a history of heart disease. The outcome of 125 metastatic breast cancer patients, with a CHF Class ≥ II according to New York Heart Association (NYHA) guidelines after an epirubicin-based treatment, was performed retrospectively. Univariate ordinal logistic regression was used to study the association between NYHA class at time of CHF (II, III or IV) and possible risk factors. Two multiple Cox regression analyses (events: mortality of cardiotoxicity and mortality of other causes) were performed to evaluate the risk of cardiac death.
Results. CHF was developed within a median time from cessation of epirubicin on 3 months (range 0 to 66.7 months). The distribution of patients in the NYHA class II, III, IV and NYHA class ≥2 was; 35 patients (28%), 38 patients (30.4%), 39 patients (31.2%) and 13 patients (10.4%), respectively. No predictive factors, including increasing cumulative dose of epirubicin, co-morbidities and age had an influence on the severity of CHF. The median survival of all patients was 7.3 months (range 0.01 to +121.1 months). Deaths caused by CHF occurred in 27 patients (21.6%) in a median time on 1.2 months (range 0 - 77 months), including 6 patients (4.8%) dying of cardiac failure &lt; 10 days after the diagnosis. Only the NYHA class patient had was the only risk factor for dying of CHF (p = 0.0003). Compared to patients in NYHA class II and III, the risk of cardiac death in patients with NYHA class IV was increased with 93% and 74%, respectively.
Survival in patients with stable CHF was comparable to other patients with metastatic breast cancer.
Discussion. Although the information is obtained retrospectively during a period of twenty years; the study is important, as only limited information is available on the course of CHF patients. The study showed that the risk of cardiac death were closely related to the degree of cardiac toxicity as the risk of cardiac death was 93% or 74% higher for patients in NYHA class IV than for patients in NYHA class II or III. Moreover, the outcome for the patients when CHF is stabilized can be expected to be as patients without CHF. Furthermore, no predictive factors were identified, including increasing cumulative dose of epirubicin for the severity of cardiotoxicity developed.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-15-04.