bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic (PK) Interactions between Lapatinib (L) and Vinorelbine (VNR) in a Phase I Study in Locally Advanced or Metastatic Breast Cancer (LAMBC) Patients(Pts) Overexpressing HER2. GEP-01 – A Study of the FNCLCC-Group of Early Phase Trials.
Authors: Lokiec F. , Brain E. , Isambert N. , Dalenc F. , Tresca P. , Bonneterre J. , Rezaï K. , Roché H. , Penel N. , Jimenez M. , Diéras V. , Fumoleau P. 
Published: December 2010

Abstract
Background: Lapatinib is effective in overexpressing HER2 LAMBC pts. Following anthracyclines, taxanes and capecitabine, VNR is an active agent in metastatic setting. Both drugs use the same main metabolic pathway: Cytochrome P450 3A4. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies, and looking for the PK interactions between the 2 drugs.Methods: Women with HER2+ LAMBC, in progression after ≤ 2 lines of trastuzumab-based treatment were treated with a 7 day (D-7 to D0) loading dose of L before starting VNR on a D1 and D8 q3w iv regimen. L was given po continuously. G-CSF as primary prophylaxis of febrile neutropenia (FN) was not permitted. Dose levels (DL) (L mg/VNR mg/m²) ranged from 750/20 to 1250/30 with 3 patients per DL. PK samples were collected on 7 points on D1 of cycle 1 for L and VNR dosages. PK time points analysis was performed on plasma for L and whole blood for VNR. For both drugs the analytical method was Ultra Performance Liquid Chromatography (UPLC) coupled with tandem mass spectrometry (MS-MS) as detection. VNR PK parameters were estimated by nonlinear mixed effect modeling (NONMEM) and L PK parameters were estimated by non compartmental software (MicroPharm).Results: Seventeen pts and 68 PK time points were available for VNR analysis. VNR was ascribed to a tri-compartment model. When considering all VNR data together, VNR clearance (CL) was 37.8±16.7 L/h, while it showed a gradual decrease according to specific dose of L: 47.5±20.4 L/h for L 750 mg (3 patients) vs 35.6±4.3 L/h for pooled data for L 1000 and 1250 (14 patients). This trend was not significant likely due to low number of patients treated at lower dose of L, while no significant difference was observed between L 1000 and L 1250. The mean elimination half life time (t1/2) of VNR was 0.12 h. Six patients and 42 PK time points were analyzed for L. L CL were respectively 83.8 ± 41.3 and 57.1 ± 5.5 L/h for patients who received 750 mg (3 patients) and 1000 mg (3 patients) of L with 20 mg of VNR. The mean elimination half life time (t1/2) of L was 2.89 h.Conclusions: A potential PK interference occurred between VNR and L. When the dose of L increased, both VNR and L CL decreased, likely due to CYP450-3A4 interactions. This trend should be confirmed by the PK analysis of L and VNR in more patients, including an intermediate DL (1250/22.5) still ongoing.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5091.
A 28-Day Intrathecal Toxicity Study with Trastuzumab in Nonhuman Primates.
Authors: Braen A. , Perron J. , Tellier P. , Catala A. , Kolaitis G. , Geng W. 
Published: December 2010

Abstract
Introduction: Trastuzumab is indicated for the treatment of patients with breast cancer whose tumors overexpress the HER2 protein. Brain metastases have been observed in breast cancer patients, being the highest in women with HER2-overexpressing tumors. The blood-brain barrier, however, may prevent trastuzumab from reaching appropriate concentrations in the cerebrospinal fluid (CSF). Case studies have been reported in which trastuzumab was intrathecally administered for the treatment of metastatic brain cancer in humans. However, no extensive preclinical safety evaluation has been performed for intrathecal application after repeat-dosing in a trastuzumab cross-reactive species using doses equivalent to or higher than those used in patients. To evaluate the potential of local effects, a 28-day toxicology study with weekly intrathecal administration of trastuzumab was performed in cynomolgus monkeys, a trastuzumab cross-reactive species. Preservative-free trastuzumab was used in this preclinical safety study, as caution has been raised for the intrathecal use of benzyl alcohol-containing solutions. Methods: Five male and five female monkeys were evaluated per dose group, of which two monkeys/sex/group were evaluated after a 4-week recovery period. Animals were assigned to 3 groups which received 4 weekly 30-minute intrathecal infusions at 0, 3, or 15 mg per dose at an infusion rate of 1.5 mL/hour. Endpoints evaluated included clinical signs, body weight, appetite, neurological examinations, clinical pathology, gross pathology, and histopathology of the brain (with inclusion of meninges), spinal cord, and infusion site. In addition, CSF and serum samples were collected for toxicokinetic evaluations. Results and Discussion: No test article-related effects on clinical signs, body weight, appetite, neurological examinations, clinical pathology, gross pathology or histopathology were noted. Of note is the absence of demyelination as was discussed as an uncertainty of intrathecally administered proteins. The doses used of 3 and 15 mg per dose resulted in 0.051 and 0.24 mg/g brain doses, respectively. Doses administered in clinical case reports ranged from 5 to 100 mg per dose. For a 1500 g human brain weight, these intrathecal doses would be equivalent to 0.0033 and 0.067 mg/g brain weight. At the high dose of 15 mg, maximum CSF concentrations (Cmax) were as high as 403 µg/mL. The applied doses and CSF concentrations achieved in the current study greatly exceeded those reported in patients (6.4 µg/mL at an intrathecal dose of 20 mg). Conclusion: The results of this 4-week toxicology study in monkeys with the results of the clinical case studies support future studies to evaluate intrathecal application of trastuzumab in patients with brain metastasis in HER2-positive breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5101.
Outcome of HER2-Positive (HER2+) Metastatic Breast Cancer Patients (MBC) Treated with Trastuzumab (T): An Institutional Based Review.
Authors: Guilhaume M. , Dieras V. , Fall M. , Pierga J. , Beuzeboc P. , Cottu P. , Simondi C. , Courbard M. , Mignot L. , Livartowski A. 
Published: December 2010

Abstract
Background: HER2+ status is associated with poor prognosis, high incidence of visceral and brain metastasis. However the addition of trastuzumab to chemotherapy (CT) significantly improves survival in early and advanced breast cancer. The purpose of this retrospective study was to explore the pattern of outcome in a cohort of MBC patients treated with T-based chemotherapy in a single institution. T was approved in Europe in 2000 and in 2001 all pts had access to T according HER2+ status. Methods: Women with de novo or recurrent breast cancer treated with trastuzumab at Institut Curie between 2001 and 2006 with HER2+ status (IHC 3+ or FISH +) were identified from the Institut Curie database. Disease was classified in two groups: patients who received T upfront and those who received T after one or several CT regimens. Overall survival (OS) was defined as the time from the date of the first metastasis to the date of death or last follow-up and was estimated using the Kaplan-Meier product method. Results: The final analysis included 244 patients. Median age was 53.4 yrs (29-80). Median time from primary and first metastasis was 22 mths (0-238). Visceral metastasis were present in 153 pts (63%) and 125 pts (51%) presented multiple sites. One hundred pts (42%) developed brain metastasis during the course of disease. One hundred and sixty five pts (68%) received T as first line, 79 pts (32%) after a median of one line of CT (median 1, range 1-5). One hundred and twenty four pts (52%) received more than 3 regimens. The median overall survival was 53 mths (4-113), similar in both groups. However there is a major bias: pts with very aggressive disease not treated upfront with T not have not been offered delayed T and don't appear in the analyzed population. Patients who developed brain metastasis had a median survival of 41 mths (11-90). Complete characteristics of pts will be presented. Conclusions: The introduction of T has altered the natural history of HER2+disease. Even outside a clinical trial, our results show that the addition of T to CT improves the prognosis of MBC patients with HER2+ disease. Prolongation of T after progression with other CT appears beneficial, even in pts with a high disease burden. The high incidence of brain metastases remains an issue in such a population.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5107.
Observational GHEA Study: Adjuvant-Trastuzumab-Treatment of HER2-Positive Breast Carcinoma.
Authors: Campiglio M. , Tagliabue E. , Balsari A. , Bufalino R. , Ferri E. , Menard S. 
Published: December 2010

Abstract
Background: GHEA (Group HErceptin in Adiuvant treatment), an Italian multicentric observational study, was designed with the aim to investigate on adjuvant trastuzumab-therapy of HER2-positive breast carcinomas in conventional clinical setting.Material and Methods: Eligible patients should have been treated with trastuzumab in adjuvant setting and were collected among 35 oncologic Italian centers.Results: The patient registered so far in the GHEA database (500 pts) had a median age of 52 years and 64% were in post-menopause at the time of trastuzumab therapy. Primary breast tumor were mainly of ductal type (93%) of high grade (59% were GIII) and small in size (58% T1, 35% T2, 4% T3 and 3% T4). 12% of the samples included in GHEA were classified as T1micro, T1a and T1b, three categories generally not included in clinical trials. ER and PgR positive tumors were 58% and 51%, respectively and more than 53% presented in situ component. Positive lymph-nodes were present in 53% of cases. 15% of the patients received neo-adjuvant therapy prior surgery and adjuvant treatment. In the neo-adjuvant therapy, 95% of patients received anthracycline–based regimens and 72% were treated with taxanes. In adjuvant setting 89% of patients received anthracycline–based regimens and only 43% were treated with taxanes. 88% of the patients completed 1-year-trastuzumab treatment. Median exposure time of the series was 26 months. To date, 6% of the patients presented distant metastasis (i.e. bones, liver, lung, SNC) and half of them progressed during trastuzumab treatment.Discussion: The purpose of the present study is to gather information from a large number of patients related to the effect of adjuvant trastuzumab treatment in conventional clinical setting, the treatment of tumor categories not included in clinical trails and the therapies used at the relapse of these patients. All together, these data are warranted to design further clinical trials to better define guide-line for trastuzumab adjuvant therapy and for the treatment of these patients at relapse.Supported by AIRC and Roche.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5112.
Pertuzumab and Trastuzumab: Re-Responses to 2 Biological Agents in Patients with HER2-Positive Breast Cancer Which Had Previously Progressed during Therapy with Each Agent Given Separately: A New Biological and Clinical Observation.
Authors: Baselga J. , Cortes J. , Fumoleau P. , Petrella T. , Gelmon K. , Verma S. , Pivot X. , Ross G. , Szado T. , Gianni L. 
Published: December 2010

Abstract
Background: Pertuzumab, a fully humanised IgG1 monoclonal antibody, is a human epidermal growth factor receptor 2 (HER2)-dimerisation inhibitor directed to the dimerisation epitope of HER2 (trastuzumab binds to the juxta-membrane epitope). Pertuzumab has demonstrated promising activity when given with trastuzumab to patients with HER2-positive metastatic breast cancer (mBC) which had progressed during therapy with trastuzumab in a 2-step Phase II study.1Methods: The protocol was amended to include a 3rd cohort of patients to determine the activity of pertuzumab when given without trastuzumab.2 Patients recruited into this 3rd cohort were allowed to have trastuzumab re-introduced in combination with pertuzumab if there was inadequate response to pertuzumab alone or response followed by relapse.Results: Twenty-nine patients were recruited into this 3rd cohort. Patients had reached their 3rd line of treatment for mBC. To date, 15 patients have had trastuzumab re-introduced after disease progression on trastuzumab therapy and pertuzumab monotherapy. Among these 15 patients, at the time of this analysis there have been 3 patients with confirmed responses. There are also 4 patients who had not yet undergone 8 cycles of assessments to reach the overall best response end point, of which at least 2 were experiencing stablisation of disease. Updated data on activity and toxicity will be presented.Conclusions: We believe this is the first time that anti-tumour activity has been reported in patients when 2 biological agents have been used together after the disease has progressed during therapy with each agent alone. There are several mechanisms which might explain this phenomenon. Trastuzumab prevents proteolytic cleavage of the extracellular domain of HER2, keeping the receptor in situ. The addition of a second antibody to a separate epitope increases the potential for antibody-dependent cell-mediated cytotoxicity and prevents dimerisation between HER2 and other HER family members, such as HER1 and HER3. The combined antibodies might increase the efficiency of inhibition of signal transduction. There are wide-ranging and potentially significant biological and clinical implications.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5114.
Risk Factor Combinations for Estimating the Probability of Breast Cancer Related Lymphedema.
Authors: Dirican A. , Wu W. , Johnson R. , Wilson J. , Soran A. 
Published: December 2010

Abstract
Background: LE is a common complication from BC surgery, leading to a decreased quality of life. In our previous study; both the risk and severity of LE were associated with 1) infection of the arm and breast, 2) body mass index (BMI), and 3) the level of hand use (p&lt;0.05 for all associations). The aim of this study was to estimate the probability of LE following BC surgery by using previously published incidence rates and the risk factors of BMI, infection, and level of hand use.Method: A retrospective review was undertaken of the 2983 women treated surgically for breast cancer at MWH of the UPMC from 1990-2000. Fifty-two women were identified for whom the diagnosis of LE was established and data existed on the study variables. The design was a n:m matched case control study; data were analyzed on 52 patients with LE and 126 available controls matched on age, radiation therapy, and type of operation. In conjunction with conditional logistic regression and published estimates of LE incidence rates, Bayes' Theorem was used to estimate the probability of developing LE. This probability was estimated for 8 combinations of BMI, infection, and level of hand use.Results: LE probabilities of 8 combinations for 6 different incidence rates of LE are shown in Table 1. For example, assuming a 16% incidence rate of LE a BMI&lt;25, no infection, and a low level of hand use; the estimated probability of LE was 6.8%. At the other extreme, assuming a LE incidence rate of 46.3%, a BMI ≥ 25, infection, and a high level of hand use led to an estimated LE probability of 93.7%. As shown in Table 1, other assumed incidence rates and risk factor combinations led to intermediate LE probabilities.Table 1 - Estimated LE probabilities for risk factor combinations according to LE incidences. AssumedLEIncidenceRate Risk Factor Combinations16%17%19.5%20.7%25.5%46.3%BMI&lt;25, No infection, Low level of hand use0.070.070.080.090.110.24BMI≥25, Infection, Medium/high level of hand use0.760.770.800.880.850.94 Conclusion: This study demonstrates that in both high and low risk situations for the development of LE that control of predisposing factors can have a marked effect on the probability of LE formation. Low risk patients with poor control of predisposing factors have a higher probability of developing LE than high risk patients in whom known predisposing factors are avoided.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5115.
Gene Expression Profiles of Endocrine Resistant Breast Tumours.
Authors: Larionov A. , Faratian D. , Caldwell H. , Sims A. , Fawkes A. , Murphy L. , Renshaw L. , Dixon J. , Dixon J. 
Published: December 2010

Abstract
AimTo identify molecular sub-classes of endocrine-resistant breast tumours.MethodsWhole genome expression profiles of 55 endocrine-resistant tumours were obtained using Illumina HT-12 BeadChip arrays. Endocrine resistance was defined as either (i) tumour increased in size during hormonal treatment or (ii) appearance of local recurrence or (iii) contra-lateral breast lesion (metastases or new cancers) during hormonal treatment. Most of the treated patients were post-menopausal. Hormonal treatment included either aromatase inhibitors (letrozole, anastrazole, arimidex) or tamoxifen.ResultsUnsupervised hierarchical clustering using 500 most variable genes split tumours into three major clusters of approximately equal size. The genes discriminating between these clusters included oestrogen receptor- and proliferation- associated set of genes (ESR1, TFF1, TFF3, FOXA1, AGR2, AGR3, XBP1, GATA3, PRAD6B, MYB, CCND1), and stroma-related genes (DCN, COL1A1, COL1A2, COL3A1, COL5A2). Initial analysis of the studied tumours was unable to identify genes associated with clinical features. Sub-division of the dataset may be required to identify these genes more clearly. Genes that tended to separate between tumours resistant to AI and Tamoxifen included MYB, GPR137B, RNF19A, FRMD6, ZNF217 and RPS12. More detailed analysis of the data is underway.DiscussionUnderstanding and overcoming of endocrine resistance will improve treatment results for the majority of breast cancer patients. This abstract reports a new gene expression dataset to compare molecular features of biopsies collected from tumours growing while on endocrine treatment. The initial analysis demonstrates diversity of the resistance mechanisms, enhancing development of individual approaches to endocrine-resistant tumours.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5132.
Redox Status Contributes to Tamoxifen-Resistant Growth of Breast Cancer.
Authors: Penney R. , Slingerland J. , Roy D. 
Published: December 2010

Abstract
The emergence of tamoxifen resistance is a major problem in the treatment of breast cancer. Tamoxifen-resistant growth coincides with a high intracellular oxidant state, and tamoxifen is known to increase intracellular oxidants in breast cancer cells. We postulate that the conversion of breast tumors to a tamoxifen-resistant phenotype is associated with a progressive shift towards a pro-oxidant environment of cells as a result of chronic antiestrogen treatment therapy. In this study, we present data that show that modifying the redox state of thioredoxin (Trx) changes the sensitivity of cells to tamoxifen, and that these changes occur through Trx-Jab1-p27 interactions. The use of ebselen on tamoxifen-resistant LCC2 breast cancer cells increased thioredoxin expression and decreased DNA synthesis in tamoxifen-treated cells. In thioredoxin reductase 2 (TrxR2)-overexpressed cells, tamoxifen inhibited in vitro tumor formation as measured by growth of colonies, and also inhibited DNA synthesis. Probing Trx in a Jab1 immunoprecipitation showed that Jab1 interacts with Trx, and that overexpression of TrxR2 results in higher Jab1-Trx interaction. Similarly, using a p27 immunoprecipitation, we found that Jab1 interacts with p27, and p27 interacts with Trx. When we knock down Jab1, we show a decrease in both colony growth and DNA synthesis in tamoxifen-treated cells. These data support our hypothesis that altering the redox status of breast cancer contributes to the restoration of tamoxifen sensitivity, and that this restoration occurs through a Trx/Jab1/p27 mechanism. The data indicate that overexpressing TrxR2 and reducing oxidized Trx increases Jab1/Trx binding, restores the inhibitory effects of p27, and restores tamoxifen sensitivity to previously resistant breast cancer cells.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5134.
2-(4-Hydroxyphenyl)-Benzo[b]thiophen-6-ol, an Estrogen-Like Compound, Induces Apoptosis in T47D/PKCα Breast Cancer Cells.
Authors: Molloy M. , Thatcher G. , Bolton J. , Tonetti D. 
Published: December 2010

Abstract
Background: Tamoxifen (TAM) treatment failure is a major obstacle encountered in the clinical setting. Our lab has previously shown that constitutive overexpression of PKCα imparts a TAM resistant/ hormone independent phenotype in the T47D:A18 breast cancer cell line. Furthermore 17β-estradiol (E2) inhibits tumor growth in vivo as well as inhibits colony formation when cells are grown in 3D Matrigel (Zhang, 2009). Before TAM treatment was introduced, breast cancer patients received high-dose E2 and diesthystilbesterol (DES) treatment. DES treated patients may have a survival advantage over TAM treated patients in the long term (Peethambaram,1999). Others have shown that E2 can have inhibitory effects on MCF-7 cells both in vitro and in vivo (Lewis-Wambi, 2009). Taken together, this suggests an estrogenic compound may be efficacious for TAM-resistant breast cancer. The present study was designed to evaluate the effect of an estrogenic compound, 2-(4-hydroxyphenyl)-benzo[b]thiophen-6-ol (BTC), related to the SERMs raloxifene and arzoxifene, on the T47D:A18/PKCα breast cancer cell line.Methods: To determine if BTC can activate estrogen regulated genes we preformed an ERE-luciferase reporter assay 24 hours after BTC treatment. 3D Matrigel colony formation assay was performed to determine if BTC could inhibit colony formation. Colonies were stained and counted on day 10. To determine if apoptosis was occurring, cells were grown in Matrigel and the TUNEL Assay was performed on Day 6.Results: T47D:A18/PKCα cells showed a 31-fold induction in ERE-luciferase reporter activity when treated with BTC (10-7M) compared to 7-fold induction when treated with E2. In the T47D:A18/Neo parental cell line, BTC induced a 40-fold induction whereas estradiol induced a 96-fold induction. In the Matrigel colony formation assay T47D:A18/PKCα cells formed significantly fewer colonies when treated with BTC. Conversely, in the T47D:A18/Neo parental cell line BTC enhanced colony formation similar to E2 treatment. Our results indicate that BTC was able to induce significant apoptosis on day 6 (P= 0.038) as determined by the TUNEL Assay. Therefore BTC acts similarly to estradiol by inhibiting T47D:A18/PKCα colony formation and inducing apoptosis when cells are grown in Matrigel.Conclusion: These findings suggest that BTC is a potential lead compound in the treatment of PKCα overexpressing breast cancer. Furthermore, BTC was shown to be a potent inducer of the cytoprotective enzyme NQO1 in the Hepa 1c1c7 cell system as well as a strong activator of antioxidant responsive elements (Yu, 2007) indicating it may have the added benefit of chemoprotective effects which are absent in estradiol treatment. Further understanding of the mechanism in which BTC induces apoptosis in the T47D:A18/PKCα cell line may result in a clinical advantage to estradiol treatment including fewer side effects.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5140.