bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trastuzumab 6 mg/kg and 4 mg/kg can be infused safely over 30 minutes.
Authors: Chan AS , Freeswick S , Sklarin NT 
Published: December 2010

Abstract
Abstract #3150
Background: Trastuzumab (T) is a humanized monoclonal antibody used in the treatment of breast cancers which overexpress the HER2 protein. Infusion-related hypersensitivity reactions (HSRs) have been reported in patients receiving T. Since T became commercially available in 1998, Memorial Sloan-Kettering Cancer Center (MSKCC) guidelines recommended that 4 and 6 mg/kg doses be infused over 90 minutes, as outlined in the product monograph. Based on more recent pharmacokinetic data of T and the experience at other institutions, it was postulated that a more rapid infusion of T would be well tolerated, even at doses greater than 2 mg/kg. As a result, in June 2007, the guideline at MSKCC was revised to infuse initial loading doses (8, 6 or 4 mg/kg) over 90 minutes and, if tolerated, all subsequent maintenance doses of 2, 4, and 6 mg/kg over 30 minutes. In this review, we sought to evaluate the safety and tolerability of T administered as a 30 minutes infusion.&#x2028; Methods: Our institutional adverse drug reaction (ADR) reporting program was used to identify HSRs possibly related to T after implementation of the new infusion time guidelines. Computerized pharmacy records were used to retrospectively identify all patients who received T at MSKCC 1 year prior to implementation of new guideline (6/06 – 5/07), as well as the period of 10 months after the implementation of the revised guideline (7/07 - 4/08). The ADRs reported before and after implementation were reviewed and compared. Additionally, patient medication administration records were reviewed to confirm reactions reported via the ADR reporting program.&#x2028; &#x2028; Results: Of the 2,633 4 and 6 mg/kg maintenance doses administered over 30 minutes, 2451 were given without concurrent administration of diphenhydramine, dexamethasone, or acetaminophen. 165 doses were escalated from 2 to 4 or 6 mg/kg and the infusion rate was kept at 30 minutes. The 2 patients with loading dose-associated HSRs, that occurred after the change in the guideline, were able to tolerate subsequent doses of T (4 and 6 mg/kg) infused over 30 minutes when rechallenged.&#x2028; Conclusion: Trastuzumab can be safely infused over 30 minutes for 4 and 6 mg/kg maintenance doses and this is the current practice at our institution. This change has resulted in improved efficiency and patient convenience, and decreased cost associated with the longer duration infusions.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3150.
Multicenter international phase II study of oral vinorelbine (NVBo), capecitabine (X) and trastuzumab (H) triple combination in HER2-positive metastatic breast cancer (MBC): updated results with a longer follow-up.
Authors: Chan A , Ganju V , Becquart D , Conte P , Petruzelka L , Gil-Gil M , Morand M , Vaissiere N , Villanova G , Tubiana-Mathieu N 
Published: December 2010

Abstract
Abstract #3151
Background: CT plus H is the standard treatment for HER2-positive MBC. Combination therapy of H plus vinorelbine is an active and safe regimen in this setting. The all-oral combination of NVBo and X has been reported as an active and safe regimen in many different trials in MBC. We report efficacy and safety information from an updated analysis of all 50 patients (pts) included in this trial, with a median follow-up of 28.5 months.&#x2028; Methods: Main eligibility criteria included: HER2-positive disease (defined as IHC 3+ or FISH+), documented measurable metastatic disease previously untreated by CT, relapse ≥ 6 months after the end of neoadjuvant or adjuvant CT, Karnofsky PS ≥ 70. NVBo was given as at a dose of 80 mg/m2 (after a first cycle at 60) D1 and D8 every 3 weeks, X at 1000 (750 if ≥ 65 years) mg/m2 bid D1-D14 every 3 weeks, H at 4 mg/kg on D1 as a loading dose then 2 mg/kg i.v. weekly starting on D8. Treatment was continued until progression.&#x2028; Results: Median age: 53.5years (18% ≥ 65); prior (neo)adjuvant CT 27 pts (54%); visceral involvement 41 pts (82%), &gt; 2 metastatic sites 17 pts (34%); Median number of cycles: 10 (range 1-56); Median relative dose intensity: NVBo 75%, X 77%, H 96%; NVBo escalated to the recommended dose of 80 mg/m2 in 84% of pts; G3/4 NCI CTC v2 adverse events per pt: (n=49) neutropenia 69%, (n=50) febrile neutropenia 8%, infection without neutropenia 4%, stomatitis 4%, nausea 4%, vomiting 12%, diarrhea 16%, hand-foot syndrome 20%, asthenia 8%, LVEF decline 6%, alopecia (grade 2) 14%; Efficacy (n=44 evaluable patients): objective response rate (RECIST) 77% (95% CI [62-89]), CR 18%, PR 59%, SD 18%, PD 5%, disease control (CR+PR+ SD ≥6 months) 93% (95% CI [81-99]), median duration of response was 14.3 months (95% CI [9.8-16.8]), median progression-free survival was 12.8 months (95% CI [10.8-16.9]), overall survival results are not mature yet. Treatment is ongoing in 5 pts.&#x2028; Conclusion: The combination of NVBo and X + H has shown high antitumoral efficacy in pts with HER2-positive MBC. Toxicity profile was acceptable with, in particular, a very low rate of alopecia. An efficacy and safety analysis in pts aged &lt; vs ≥ 65 years will be performed and presented.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3151.
HER2 and HER3 cooperatively regulate tumor cell growth and determine sensitivity to the HER kinase inhibitor TAK-285.
Authors: Takagi S , Hayashi A , Ohta Y 
Published: December 2010

Abstract
Abstract #3155
Background: The HER (ErbB) receptor family plays a major role in the proliferation of tumor cells. Overexpression of these receptors occurs in breast and a variety of cancers and correlates with poor prognosis. We have identified TAK-285, a potent, selective and orally bioavailable small molecule inhibitor of HER kinases. TAK-285, which is currently in clinical trials for the treatment of solid tumors, inhibits EGFR (also known as ErbB1 or HER1) and HER2 (also known as ErbB2) and exerts clear anti-proliferative activity in in vitro and in vivo tumor models. Here, we elucidated the determinants of TAK-285 anti-tumor activity in vitro in a panel of human cancer cell lines.&#x2028; Methods: Cell growth inhibition assay was performed using sulforodamine B staining method or CellTiter-GloTM assay (Promega). Candidate gene expressions were measured by quantitative PCR. Associations between the IC50 values and the candidate gene expressions were statistically analysed.&#x2028; Results: TAK-285 exerted anti-proliferative effects in all of cell lines tested in a dose dependent manner but the effects ranged widely (IC50: 0.011-over 10 µmol/L). Statistical analysis showed an inverse correlation between sensitivity to TAK-285 (IC50 values) and HER2 or HER3 (also known as ErbB3) gene expression. PTEN or IGF-1R gene expression, reported to be involved in trastuzumab resistance, was not correlated with TAK-285 sensitivity. Immunoblot analysis revealed that HER2 and HER3 are coexpressed in most TAK-285 sensitive cells and TAK-285 inhibited phosphorylation of HER3. Because HER3 does not possess kinase activity, this suggests that HER3 is trans-phosphorylated by HER2. Knockdown of HER3 using siRNA inhibited tumor cell growth in TAK-285 sensitive cells but not in TAK-285 insensitive cells.&#x2028; Conclusion: These results suggest that HER2 and HER3 mainly regulate tumor cell growth in TAK-285 sensitive cells and could be used as a molecular marker to select patients who are likely to respond to TAK-285.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3155.
A multicenter phase II study of non-pegylated liposomal doxorubicin (MYOCET®) in combination with trastuzumab and docetaxel as first line therapy in metastatic breast cancer.
Authors: Vanturini M , Bighin C , Puglisi F , Contu A , Aitini E , Colucci G , Merlano MC , Paccagnella A , Marini G , Crinò L , Djazouli K , Barbato A 
Published: December 2010

Abstract
Abstract #3156
The objective of the phase II study is to evaluate the cardiotoxicity, general safety, and efficacy of non-pegylated liposomal doxorubicin, in combination with docetaxel and trastuzumab, as first line treatment of metastatic breast cancer.&#x2028; Patients and methods: Patients (n = 31) with metastatic HER2-overexpressing breast cancer, who had not previously received chemotherapy for metastatic disease, received non-pegylated liposomal doxorubicin (50 mg/m2), docetaxel (75 mg/m2) every 3 weeks and trastuzumab (2 mg/kg/week) for up to eight cycles, followed by trastuzumab alone for up to 52 weeks. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure (CHF) and/or an absolute decrease in left ventricular ejection fraction (LVEF) of ≥ 20 units or a decline to ≤ 45%. Patients were allowed to receive adjuvant doxorubicin or epirubicin to cumulative doses up to 240 mg/m2 or 450 mg/m2, respectively.&#x2028; Results: The mean LVEF at baseline was 62.8 ± 7.1% and decreased to 60.2 ± 6.5% at cycle 2, but did not change significantly during the rest of the study; mean values at cycle 8 and at the end of the study were 58.7 ± 7.0% and 57.3 ± 9.5% respectively. One case of symptomatic CHF occurred during the study.&#x2028; The most common adverse events were hematologic toxicities, alopecia, asthenia and fever. The Overall Response Rate was 65.5% (CR 31%, PR 34.5%).The median progression free survival was 15.5 months (95% CI 11-24 months). The average overall survival was 27.9 months.Conclusions: These results suggest that the combination of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab has shown a good cardiac safety profile at a long term follow up, comparatively to recent published results data in HET study. A promising efficacy including CR and PFS has been noted in 1st line MBC.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3156.
HER2 positive early breast cancers: tumour demographics and trastuzumab therapy in the real-world.
Authors: Marla S , Roxburgh P , Burton P , Stallard S , Mallon E , Canney P , Cooke T 
Published: December 2010

Abstract
Abstract #3159
Background: Various trials have shown substantial benefits of addition of Trastuzumab (Herceptin®) to adjuvant chemotherapy in Early Breast Cancer (EBC). We analysed our breast cancer population to determine the incidence of HER2 positive Early Breast Cancers, the tumour demographics and the number of patients eligible for and receiving trastuzumab therapy in this group.&#x2028; Methods: Data for all patients diagnosed with EBC in 2006 was recorded prospectively in a database. Case notes were consulted where the HER2 positive patients, determined by a combination of IHC and FISH, had not received trastuzumab, to ascertain the reasons.&#x2028; Results: A total of 951 patients were diagnosed with Breast Cancer in 2006. 417 (43.9%) of these were screen-detected cancers.&#x2028; There were 123 (12.9%) HER2 positive newly diagnosed Breast Cancers of whom 117 were EBCs. The HER2 positivity rate in the screen detected cancers (n=417) was 9% and 17% in the symptomatic cancers (n=433).&#x2028; 1. Demographics of the HER2 positive Early Breast Cancer Population:&#x2028; The median age at diagnosis was 61 yrs (range: 30-92).&#x2028; &#x2028; 2. Fifty nine (50.4%) of the HER2 positive EBCs received trastuzumab therapy.&#x2028; &#x2028; Conclusions: The HER2 positivity rate is lower than that previously reported suggestive of changing demographics secondary to a high screen detected cancer population. A third of the HER2 positive tumours are screen detected. The percentage of ER positive, node negative and low grade tumours was higher than anticipated.&#x2028; Only 50% of HER 2 positive EBC patients received trastuzumab therapy. Of those who did not receive trastuzumab, the commonest reason was low risk status or age and co-morbidities precluded chemotherapy.&#x2028; HER 2 positivity alone confers high risk irrespective of pathological stage. Further trials are required to evaluate whether the substantial number of patients who are at present not eligible for trastuzumab therapy might also benefit.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3159.
HER2 protein expression predicts response to trastuzumab in FISH-positive patients.
Authors: Lipton A , Ali SM , Leitzel K , Koestler W , Fuchs E , Weidler J , Wu E , Sperinde J , Chappey C , Huang W , Bates M 
Published: December 2010

Abstract
Abstract #32
BACKGROUND: Fluorescent in Situ Hybridization (FISH) is currently employed to select patients for trastuzumab or lapatinib therapy. However, only a portion of patients will respond to these HER2-directed therapies. Using a novel assay to quantitate total HER2 (H2T) and HER2 homodimer (H2D) levels, we examined the relationship between these measurements and clinical outcomes in a cohort of trastuzumab-treated metastatic breast cancer patients previously assessed as FISH positive by central testing.&#x2028; METHODS: The VeraTag assay was used to measure H2T and H2D. A cutoff previously defined by positional scanning was used to classify patients as H2T high or low (Leitzel et al. ASCO abstract # 1002, 2008). FISH status was determined using the Vysis assay and was performed by a single pathologist under standardized conditions (central testing). FISH + was defined as HER2/CEP17 ratio greater than 2.2. Kaplan-Meier and Cox proportional hazards analyses (TTP and OS) were conducted.&#x2028; RESULTS: 99 MBC patients previously scored as IHC 3+ or 2+, FISH+ and treated with first line trastuzumab-containing regimens were re-tested by central FISH. 22 patients were found to be FISH- and 77 were FISH+. 67 FISH+ patients had high H2T levels, and 19 FISH- patients were H2T low. 14% (3/22) of FISH- patients were H2T high, and 13% (10/77) of FISH+ patients were H2T low (overall discordance rate = 13%). In Kaplan Meier analyses, patients assessed as FISH+, H2T high had a significantly longer TTP (median TTP=11.3 mos.) compared to those who were FISH-, H2T low (median TTP=4.5 mos. HR=0.42, p=0.0006), and also compared to those who were FISH+, H2T low (median TTP=3.7 mos. HR=0.43, p=0.01). Those patients who had discordant results (FISH+, but H2T low) behaved similarly compared with FISH-, H2T low (HR=1, p=0.99). Similar results were observed using H2D. In analyses restricted to central FISH+ patients only (N=77), Cox proportional hazards multivariate regression identified H2T as an independent predictor of TTP (HR=0.29, p=0.0015) and OS (HR=0.37, p=0.02).&#x2028; CONCLUSION: In metastatic breast cancer patients previously assessed as FISH-positive by central testing, we observed an approximate 55-fold distribution of HER2 protein expression. Patients with HER2 gene amplification by FISH but low HER2 total protein expression or homodimer levels as measured by the VeraTag assay respond poorly to trastuzumab-containing therapy.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 32.
PI3 kinase activation and response to trastuzumab or lapatinib in HER-2 overexpressing locally advanced breast cancer (LABC).
Authors: Migliaccio I , Gutierrez M , Wu M , Wong H , Pavlick A , Hilsenbeck SG , Horlings HM , Rimawi M , Berns K , Bernards R , Osborne C , Arteaga CL , Chang JC 
Published: December 2010

Abstract
Abstract #34
Background: Activating mutations of PI3 kinase (PIK3CA) and PTEN loss may be associated with trastuzumab resistance. Trastuzumab, a HER2 humanized monoclonal antibody, and lapatinib, an EGFR/HER2 tyrosine kinase inhibitor are both established treatments. Greater understanding of the cellular response to trastuzumab or lapatinib is needed to tailor targeted therapy for individual patients and identify those less likely to benefit. Material and Methods: We performed two sequential neoadjuvant clinical trials in HER-2 overexpressing LABC: 40 patients received weekly trastuzumab at standard doses given initially as a single agent for the first 3 weeks, then in combination with 3-weekly docetaxel for 12 weeks (T), while 49 patients received lapatinib as a single agent (1,500 mg daily, orally) for 6weeks then the combination of 3-weekly trastuzumab/docetaxel for 12 weeks, before primary surgery (L). Sequential core biopsies of the primary breast tumors were taken at initial, weeks 1 and 3 after the first dose of trastuzumab, and at initial, weeks 2, 4, and 6 after lapatinib. Apoptosis, Ki67 proliferation rate, and PTEN were assessed by immunohistochemistry. Low PTEN was defined as Allred score of &lt;3. Genomic DNA (10-100ng) was sequenced using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems) and an ABI 3730 automated capillary sequencer. Two sample and paired sample comparisons were performed using nonparametric tests. Results: There was a significant decrease in clinical tumor size after three weeks of trastuzumab (n=35, median=-20%), and six weeks of lapatinib (n=49, median=-74%) compared to pre-therapy (p&lt;0.001). At surgery, pathologic complete response was observed in 38% in patients on upfront T and 70% patient on L. There was a significant increase in apoptosis (median=3.5% to 4.7%, p=0.006) within one week after trastuzumab, with no significant change in Ki67 at any of the time point. Lapatinib was associated with a no significant increase in apoptosis but a significant decrease in Ki67 at week 2, 4, and 6 of therapy (p&lt;0.001). Cases with low PTEN or PIK3CA mutations were significantly less likely to have a pathologic complete response to T (p&lt;0.005). Howver, low PTEN or PIK3CA mutations was not significantly associated with pathologic resistance to L. Conclusions: Activation of PI3 kinase pathway is associated with trastuzumab but not lapatinib resistance. Lapatinib may affect signalling through the Ras/Raf/MAPK/ERK pathway, inhibiting cell division. Low PTEN expression was not associated with lapatinib resistance, and may explain the clinical efficacy of lapatinib in trastuzumab-resistant patients, supporting clinical trials for the combination of both agents.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 34.
Transforming growth factor beta engages TACE/ADAM17 and ErbB3 to activate PI3K/Akt in HER2-overexpressing breast cancer and desensitizes cells to trastuzumab.
Authors: Wang E , Xiang B , Olivares MG , Chung C , Arteaga CL 
Published: December 2010

Abstract
Abstract #35
TGFb signaling synergizes with HER2 in breast cancer progression. Exogenous TGFb or expression of an activated TGFb type I receptor (Alk5T204D) in MCF10A/HER2 and BT474 cells activated PI3K/Akt and enhanced survival and migration. In both cell types, TGFb stimulated P-EGFR and P-HER2 as well as the association of p85, the regulatory subunit of PI3K, with Y1289 P-ErbB3 which, in turn, activated PI3K/Akt. RNA interference of ErbB3 or treatment with pertuzumab, an antibody that blocks HER2-mediated activation of ErbB3, blocked TGFb-induced P-ErbB3, P-Akt, and cell motility. Treatment with TGFb or expression of Alk5TD increased protein levels of secreted TGFalpha, amphiregulin, and heregulin without a change in mRNA levels. The increase on secreted ErbB ligands without a change in mRNA levels suggested increased shedding of ErbB pro-ligands by tumor necrosis factor a-converting enzyme (TACE). Transfection of siRNA against human TACE but not control siRNA abrogated TGFb-stimulated ErbB receptor phosphorylation, P-Akt, and cell invasiveness. Transfection of full-length mouse TACE but not truncated TACE lacking the cytoplasmic domain reconstituted TGFb-induced ErbB phosphorylation in cells transfected with human TACE siRNA. TGF-b increased TACE phosphorylation in both serine and threonine as measured by P-Ser and P-Thr immunoblots of TACE pull downs. Incubation of TACE with Alk5TD in the presence of ATP in vitro resulted in both Ser and Thr phosphorylation in full-length but not truncated TACE. Further, addition of TGFb or expression of Alk5TD desensitized SKBR3 and BT474 cells to trastuzumab. Treatment with the type I TGFb receptor (Alk5) small molecule inhibitor LY2109761, the PI3K inhibitor LY294002, or siRNA against ErbB3 or TACE restored the inhibitory effect of trastuzumab. Finally, we generated an active Alk5 expression signature by selecting genes that were differentially expressed between BT474/Alk5TD and BT474/vector cells. Mapping of this signature to a previously published 295-breast tumor array (van de Vijver et al. and Chang et al.) revealed 90 of 271 genes in the Alk5TD signature with a &gt;1.5-fold change from the median expression which correlated with HER2-positive and basal-like tumors and conferred a worse recurrence-free (RFS) and overall survival (OS) (RFS p=0.05, OS p=0.01). Hierarchical clustering analysis to an array data set reported by Harris et al. in 22 patients with HER2+ breast cancer treated with neoadjuvant trastuzumab and vinorelbine (Clin. Cancer Res. 2007) showed that the Alk5TD signature correlated with tumors that did not respond clinically. These data suggest that TGFb potentiates signaling downstream ErbB receptors via TACE, ErbB3, and PI3K, thus contributing to tumor progression and resistance to anti-HER2 therapies.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 35.
The role of real-time virtual sonography in the management of enhancing breast lesions on contrast-enhanced MRI.
Authors: Nakano S , Fujii K , Yorozuya K , Mouri Y , Fukutomi T , Ishiguchi T , Arai O , Mitake T 
Published: December 2010

Abstract
Abstract #4001
[Purpose]&#x2028; The aim of this study was to evaluate the role of real-time virtual sonography (RVS) in the management of enhancing breast lesions visualized with contrast-enhanced MRI.&#x2028; [Materials]&#x2028; Between April 2006 and May 2008, 92 women underwent breast MRI at our hospital. Of these 92 patients, 55 underwent MRI for staging of known breast cancer, and the remaining 37 underwent MRI for problem solving, including abnormal findings at physical examination or on conventional images. All patients were examined using mammography, sonography, MRI and RVS. The RVS system is capable of superimposing a sonography image with the MRI image of the same section in real time using a position tracking system with a magnetic sensor. Breast MR images were obtained on a 1.5-T imager using a flexible body surface coil, with the patient in the supine position.&#x2028; [Results]&#x2028; Overall sensitivity for detecting primary breast cancer was 74% (43/58) for mammography, 93% (54/58) for sonography, 97% (56/58) for MRI, and 97% (56/58) for RVS. Incidental enhancing / suspicious lesions (IELs) which were not predicted by the previous conventional imaging techniques were found in 55% of the patients (51/92),. Of these, 59% (24/41) of IELs could be identified only on repeated sonography, but 85% (35/41) of them were identified easily using the RVS system (p&lt;0.05). The RVS system was able to project enhanced MRI information onto a body surface correctly while checking sonography form images without the use of large-scale equipment. Histologically, 10% (4/41) of the IELs were invasive ductal carcinoma.&#x2028; [Conclusions]&#x2028; The present results suggest that the RVS system offers excellent accuracy for identification of enhancing breast lesions. RVS can accurately select the cases in which MR guided biopsies are required.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4001.