494 results on '"Véronique Diéras"'
Search Results
452. RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC)
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Nicholas J. Robert, John A. Glaspy, Denise A. Yardley, Oleg Lipatov, E. A. Perez, Adam Brufsky, X. Zhou, Igor Bondarenko, S. Phan, and Véronique Diéras
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Taxane ,Anthracycline ,Bevacizumab ,business.industry ,medicine.medical_treatment ,medicine.disease ,Metastatic breast cancer ,Capecitabine ,Docetaxel ,Internal medicine ,Clinical endpoint ,Medicine ,business ,medicine.drug - Abstract
1005 Background: B in combination with weekly paclitaxel or docetaxel (D) as 1st-line therapy for MBC has improved progression-free survival (PFS) compared with the respective taxane alone in two large Phase III trials. This study investigated the addition of B to standard 1st-line chemotherapy regimens for MBC. Methods: Patients were randomized in 2:1 ratio to receive B + chemotherapy or placebo (pl) + chemotherapy. Prior to randomization, investigators chose capecitabine (Cap) (2000 mg/m2 x 14d), taxane (T) (nab-paclitaxel [260 mg/m2] or D [75 or 100 mg/m2], q3wk), or anthracycline (Ant)-based chemotherapy (q3wk). B or pl was administered at 15 mg/kg q3wk. Key eligibility criteria included MBC or locally-recurrent disease, no prior cytotoxic treatment, ECOG PS 0 or 1, HER2-negative disease and no CNS metastases. The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival (OS), objective response rate (ORR), independent review of PFS, and safety. At progression, all patients were eligible for B with 2nd line chemotherapy. The Cap cohort and the pooled T or Ant (T + Ant) cohort were independently powered and analyzed in parallel using two-sided stratified log-rank test (Cap: 80% power to detect HR=0.75; T + Ant: 90% power to detect HR=0.7). Results: RIBBON-1 enrolled 1237 patients (Cap, 615; T, 307; Ant, 315) from 12/05 to 8/07 in 22 countries with a median follow-up of 15.6 months in the Cap cohort and 19.2 months in the T + Ant cohort. The results are summarized below. OS data are limited with only 33% of events. Safety was consistent with results of prior B trials. Conclusions: The addition of B to Cap, T; or Ant-based chemotherapy regimens used in 1st-line treatment of MBC resulted in statistically-significant improvement in PFS with a safety profile comparable to prior Phase III studies. [Table: see text] [Table: see text]
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- 2009
453. Safety and efficacy of neratinib (HKI-272) in combination with vinorelbine in patients with solid tumors
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D.L. Hershman, Christine Powell, Véronique Diéras, Ahmad Awada, J. Beck, V. Agrapart, F. Binlich, C. Germa, Luc Dirix, and S. A. Limentani
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Antitumor activity ,Cancer Research ,business.industry ,medicine.drug_class ,Vinorelbine ,Tyrosine-kinase inhibitor ,Oncology ,Trastuzumab ,Neratinib ,Cancer research ,Medicine ,In patient ,business ,medicine.drug - Abstract
e14554 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor. Preclinical studies have shown synergistic antitumor activity with the combination of trastuzumab plus vinorelbine in metastatic breast cancer.The recommended dose of neratinib in monotherapy is 240 mg. In this phase 1 study, a combination dose of neratinib plus vinorelbine that is tolerable was determined in patients (pts) with solid tumors. Methods: This is an open-label, 2-part study of ascending multiple daily oral doses of neratinib (160 mg, 240 mg) in combination with 25 mg/m2 IV vinorelbine (administered on days 1, 8 every 3 wks). Tumor measurements were made every 6 wks by modified RECIST criteria. Results: 6 pts have been treated at each dose level. Data for 12 pts (5 pts still ongoing) as of 30 Oct 2008 are presented (median age [range] of 53.5 [38–75] yrs; 83% female). The median duration of treatment [range] was 1.9 [1.5–2.7] m. There was only 1 dose limiting toxicity (DLT) of grade 3 neuropathy (pt had preexisting grade 1 neuropathy) at 160 mg neratinib-25 mg/m2 vinorelbine, so the dose was escalated to 240 mg neratinib- 25 mg/m2 vinorelbine. In this cohort, there were no DLTs, and since the neratinib and vinorelbine doses reached full standard doses there was no need for further dose escalation. AEs, any causality, all grades in ≥ 15% of pts included diarrhea (92%), nausea (67%), constipation (50%), fatigue (42%), vomiting and anthralgia (33% each), abdominal pain and anorexia, (25% each), anemia and neutropenia (17% each). Grade ≥3 AEs that occurred in ≥1 pt included neutropenia (2 pts), pneumonia (1 pt) and peripheral neuropathy (2 pts). Preliminary efficacy data show that 1 pt with stomach cancer had stable disease, lasting ≥21 weeks. Conclusions: The combination of 240 mg neratinib and 25 mg/m2 vinorelbine was found to be tolerable and to demonstrate early evidence of clinical benefit in pts with solid tumors, to be assessed further in pts with metastatic ErbB-2+ breast cancer in part 2. [Table: see text]
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- 2009
454. Neratinib in combination with trastuzumab for the treatment of advanced breast cancer: A phase I/II study
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Charles Zacharchuk, Zefei Jiang, Véronique Diéras, Richat Abbas, Christine Powell, Yan Sun, Kimberly L. Blackwell, R. Swaby, K. Zaman, and Manisha Thakuria
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Phases of clinical research ,Cancer ,Pharmacology ,medicine.disease ,Loading dose ,Breast cancer ,Trastuzumab ,Internal medicine ,Neratinib ,medicine ,Clinical endpoint ,Progression-free survival ,business ,medicine.drug - Abstract
1004 Background: Neratinib (HKI-272) is an orally administered irreversible pan-ErbB receptor tyrosine kinase inhibitor. In an ongoing phase II study, the preliminary objective response rate was 26% in patients with ErbB2+ advanced breast cancer with prior trastuzumab therapy. This study assessed the safety and preliminary efficacy of the combination of neratinib plus trastuzumab. Methods: Patients with advanced ErbB2+ breast cancer that progressed following trastuzumab therapy were enrolled. The primary endpoint was 16-week progression free survival rate (PFS). In part 1 (dose escalation), patients received neratinib 160 mg or 240 mg daily plus trastuzumab 4 mg/kg IV loading dose then 2 mg/kg weekly. In part 2, patients received weekly trastuzumab with neratinib 240 mg daily. Timed blood samples were collected for PK analyses. PK analysis is ongoing. Results: 45 patients (part 1 n = 8; part 2 n = 37) were enrolled (mean age 52 yr); 9 are active. In part 1, cohorts 1 and 2 were fully enrolled with 4 patients each. No dose limiting toxicities were observed. Most common AEs, any grade, were diarrhea (91%), nausea (51%), anorexia (40%), vomiting (38%), and asthenia (27%). Grade 3/4 AEs were diarrhea (13%), nausea (4%), vomiting (4%). Two patients receiving neratinib 240 mg reported AEs leading to withdrawal. No AEs of congestive heart failure and no significant drops of left ventricular ejection fraction were reported. Among 33 patients evaluable for efficacy, objective response rate was 27% (95% CI, 13% - 46%); 16-week PFS rate (for part 2) 47% (95% CI, 29% - 63%); median PFS was 19 weeks (95% CI 15 - 32 weeks). Conclusions: Neratinib plus trastuzumab was well tolerated with no significant or unexpected toxicities, and demonstrated clinical activity. [Table: see text]
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- 2009
455. GEP01: A phase I study of lapatinib (L) and vinorelbine (VNR) in HER2 overexpressing (HER2+) locally advanced or metastatic breast cancer (LAMBC) patients (pts): A FNCLCC Group of early phase trials study
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Keyvan Rezai, Véronique Diéras, Florence Dalenc, F Mefti-Lacheraf, François Lokiec, P. Fumoleau, H. Roche, E. Brain, J. Bonneterre, and Marta Jimenez
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Neutropenia ,Pharmacology ,Lapatinib ,medicine.disease ,Vinorelbine ,Metastatic breast cancer ,Loading dose ,Capecitabine ,Regimen ,Internal medicine ,medicine ,business ,Febrile neutropenia ,medicine.drug - Abstract
1051 Background: Lapatinib is an effective anti-HER-2 therapy in LAMBC pts, currently investigated in the adjuvant setting. Following anthracyclines, taxanes and capecitabine, VNR is an active agent in metastatic setting. Its main toxicity consists of neutropenia and may challenge the standard weekly, day D1 and D8 regimen. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies and the potential pharmacokinetic (PK) interactions. Methods: Women with a HER-2+ LAMBC, in progression after ≤ 2 lines of trastuzumab-based treatment were treated with a 7D (D-7 to D0) loading dose of L before starting VNR on a D1 and D8 q3w IV regimen. L was given orally continuously. Primary prophylaxis of febrile neutropenia (FN) with G-CSF was not permitted. Dose levels (DL, L [mg]/VNR [mg/m2]) ranged from 750/20 to 1250/30 with 3 pts/DL (6 in case of dose-limiting toxicity [DLT]). DLT was defined on tolerance at cycle 1 and included grade (gr) 4 neutropenia (PN) ≥ 7D, FN, thrombocytopenia (gr4 or symptomatic gr3), omission of D8 for haematological toxicity, and any drug-related gr3–4 non-haematological toxicity. PK samples were collected on 7 points on D1 of cycle 1 for L and VNR dosages. Results: From August 2007 to December 2008, 15 evaluable pts were enrolled (median age 58 [46–75], 43% PS 0, 8 pts previously exposed to only 1 line of trastuzumab) and 65 cycles were administered. Toxicity is available for 13 pts. Of 3 pts treated at DL4 (1000/25), 2 developed a DLT: 1 FN and 1 gr4 PN > 7D. Other significant toxicities (% pts) included gr2 anaemia 8%, gr4 PN 46%, gr1 diarrhoea 62%, gr2 nausea/vomiting 8%, gr1 skin rash 23%, gr2 transaminases 23%; no decrease of cardiac function occurred. From DL1 to DL3 (750/20, 1000/22.5), total body clearance of VNR decreased by 50% (32 ± 19 L/h vs 17 ± 7 L/h). Conclusions: Maximal tolerated dose has been reached at 1000/22.5 for the combination of L with VNR given on a D1 and D8 q3w schedule. Given a potential PK interference which would yield to higher exposure to VNR, an intermediate DL is going to be explored (1250/22.5) to allow an accurate definition of the recommanded dose of the combination for future phase II comparison studies. [Table: see text]
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- 2009
456. Meningeal carcinomatosis in patients with breast cancer: clinical features and prognostic factors in 91 patients from a single institution
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F-C Bidard, Laurent Mignot, J-Y Pierga, M.N. Guilhaume, Alain Livartowski, H Gautier, and Véronique Diéras
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Ductal carcinoma ,medicine.disease ,Gastroenterology ,Primary tumor ,Folinic acid ,Meningeal carcinomatosis ,Breast cancer ,Internal medicine ,medicine ,Methotrexate ,business ,Prospective cohort study ,medicine.drug - Abstract
Abstract #1090 Background Breast cancer is the leading solid tumor responsible for meningeal carcinomatosis (MC) and the incidence is rising. To date, there is no standard of care and few prospective trials. Intrathecal treatment is provided but the modalities remain controversial. Methods From our data base we recorded 91 patients with breast MC admitted to Institut Curie between 2000-2007. Lumbar punction was performed in all patients for cerebrospinal fluid (CSF) cytology, protein level and dosage of CYFRA 21. Intra-thecal treatment: methotrexate 15 mg day1 to 5 and hydrocortisone acetate day 1 with oral folinic acid rescue day 1 to 5 every two weeks. Results Median age was 53 years (range 30-78). Tumor type was ductal carcinoma (63%), lobular (28%), ER positive 74%, HER2 overexpressed 10% and triple negative 31%. All patients presented other metastatic site: bone (67%), liver (42%) lung (29%), brain (38%). The median interval between primary tumor and diagnosis of MC was 60 months. Amongst the 80 patients treated (87%) with intra-thecal MTX, clinical response was observed in 88% of cases. There was a strong correlation between clinical response and survival (p 1 year) or patients for whom treatment will have no impact on survival (< 3 months). Conclusion: This score has to be confirmed in prospective study and new modalities of treatments need to be evaluated according to the biology of disease. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1090.
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- 2009
457. Multicenter phase I clinical trial of daily and weekly RAD001 (everolimus) in combination with vinorelbine and trastuzumab in patients with HER-2-overexpressing metastatic breast cancer with prior resistance to trastuzumab
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Angelica Fasolo, G. Jerusalem, Tarek Sahmoud, Luca Gianni, L. Vittori, Joop P. W. van den Bergh, Fatima Cardoso, I Pylvaenaeinen, Véronique Diéras, and A. Rorive
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Cancer Research ,medicine.medical_specialty ,Everolimus ,business.industry ,Urology ,Cancer ,Phases of clinical research ,Pharmacology ,Neutropenia ,medicine.disease ,Vinorelbine ,Loading dose ,Metastatic breast cancer ,Oncology ,Trastuzumab ,medicine ,business ,medicine.drug - Abstract
Abstract #406 Background: Resistance to trastuzumab (H) is associated with loss of PTEN and AKT/mTOR activation. Preclinically, RAD001, an oral inhibitor of mTOR, enhances the efficacy of H suggesting that RAD001 could reverse resistance to H. Methods: Vinorelbine (V) was administered at a dose of 25 mg/m2, IV over 10-15 min on days 1 and 8 q3w. H 4 mg/kg loading dose administered IV over 90 min on Day 1 (if pt was not already receiving H), followed by weekly H 2 mg/kg IV over 30 min. In the daily RAD001 arm, 3 cohorts were planned (2.5, 5 and 10mg) and in the weekly RAD001 arm, 4 cohorts were planned (20, 30, 50 and 70mg). Treatment continued until progression or unacceptable toxicity. Results: As of June 10 2008, 28 heavily pretreated pts were enrolled: 15 to 5mg/d, 6 to 20mg/w and 7 to 30mg/w cohorts. All pts received prior taxanes. Median number of prior CT regimens was 3 (range: 1-5). The main safety events were grade 2 and 3 stomatitis which led to dose reduction of RAD001 in 3 pts and dose interruption in 3. Grade 4 and 3 Neutropenia were seen in 24 pts (leading to dose reduction of V in 11 pts). Twenty two pts have been evaluated for efficacy (table 1). 1 pt had a CR (45+ weeks), 2 pts had PR (35+, 38 weeks), 15 pts SD (Median 26+, range 8+ to 58 weeks) and 4 pts PD. Clinical benefit rate (CR+PR+SD > 24 wks) is 55%+. Conclusions: Initial findings show that RAD001 is generally well tolerated in combination with V and H and shows promising anticancer activity and clinical benefit in heavily pretreated patients with HER2+ advanced breast cancer. Updated results will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 406.
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- 2009
458. Neoadjuvant chemotherapy for breast cancer (BC): is doxorubicin-cyclophosphamide (AC) combination still a standard regimen?
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P. Kerbrat, Pierre Pouillart, Gilles Romieu, Moïse Namer, P. Fumoleau, M. Tubiana-Hulin, Véronique Diéras, L. Mauriac, J.P. Guastalla, and A. Martinez
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Doxorubicin/Cyclophosphamide ,medicine.disease ,Regimen ,Breast cancer ,Internal medicine ,medicine ,business - Published
- 1999
459. Multicenter phase I clinical trial of daily and weekly RAD001 in combination with vinorelbine and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with prior resistance to trastuzumab
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Angelica Fasolo, Tarek Sahmoud, Jonas Bergh, Luca Gianni, Véronique Diéras, A. Rorive, Guy Jerusalem, C. Manlius, Fatima Cardoso, and I. Pylvaenaeinen
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Cancer Research ,Everolimus ,business.industry ,Letrozole ,Phases of clinical research ,Pharmacology ,Vinorelbine ,medicine.disease ,Metastatic breast cancer ,Breast cancer ,Oncology ,Trastuzumab ,medicine ,skin and connective tissue diseases ,business ,PI3K/AKT/mTOR pathway ,medicine.drug - Abstract
1057 Background: RAD001 (everolimus) is an oral inhibitor of the mTOR serine-threonine kinase, a downstream component of the PI3K/AKT signaling pathway playing a critical role in regulation of protein synthesis and ultimately cell growth, proliferation, and angiogenesis. RAD001 shows activity in breast cancer patients (pts) as both monotherapy and in combination with letrozole. Preclinical models demonstrate that RAD001 enhances the efficacy of trastuzumab. Loss of PTEN and AKT/mTOR activation have been reported to mediate resistance to trastuzumab. Methods: Vinorelbine was administered at a dose of 25 mg/m2, IV over 10–15 min on days 1 and 8 q3w. Trastuzumab 4 mg/kg loading dose administered IV over 90 min on day 1 (if pt was not already receiving trastuzumab), followed by weekly trastuzumab 2 mg/kg IV over 30 min. In the daily RAD001 arm, 2 cohorts were planned (5 and 10mg) and in the weekly RAD001 arm, 4 cohorts were planned (20, 30, 50 and 70mg). Treatment continues until progression or unacceptable t...
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- 2008
460. A physician-reported neurological signs and symptoms worksheet (NSS WS) in EGF105084: A phase II study of lapatinib (lap) for pts with recurrent brain metastases (BM) from HER2+ breast cancer (BC)
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Henri Roché, D. Zembryki, Véronique Diéras, B. Dharan, H. J. Stemmler, Minetta C. Liu, D. Skarlos, Nan Lin, Stephen D. Rubin, and K. Stepewski
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Neurological signs ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.product_category ,business.industry ,Phases of clinical research ,medicine.disease ,Lapatinib ,Surgery ,Breast cancer ,Internal medicine ,medicine ,business ,Worksheet ,medicine.drug - Abstract
1078 Background: BM are frequently accompanied by a variety of NSS. Development of a systematic assessment tool for NSS may aid in the evaluation of clinical benefit. Based on a list of tumor-relat...
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- 2008
461. Larotaxel (L) in combination with trastuzumab in patients with HER2 + metastatic breast cancer (MBC): Interim analysis of an open phase II label study
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Patrice Viens, Ahmad Awada, E. Lidbrink, H. Roche, D. Mery-Mignard, Corinne Veyret, Gilles Romieu, Véronique Diéras, Hervé Bonnefoi, and Florence Dalenc
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Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,business.industry ,medicine.disease ,Interim analysis ,Metastatic breast cancer ,Larotaxel ,Taxoid ,Trastuzumab ,Internal medicine ,medicine ,In patient ,business ,medicine.drug - Abstract
1070 Background: Larotaxel (L), a semi-synthetic taxoid, has shown preclinical and clinical activity against taxane-resistant BC, and it presents the ability to cross the blood brain barrier. In HE...
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- 2008
462. EGF105084, a phase II study of lapatinib for brain metastases in patients (pts) with HER2+ breast cancer following trastuzumab (H) based systemic therapy and cranial radiotherapy (RT)
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D. Lossignol, Véronique Diéras, Nan Lin, D. Paul, C. Christodoulou, Henri Roché, D. Laessig, Eric P. Winer, D. Zembryki, and Cristina Oliva
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Oncology ,Cancer Research ,medicine.medical_specialty ,Cranial radiotherapy ,business.industry ,Incidence (epidemiology) ,Phases of clinical research ,Lapatinib ,medicine.disease ,Systemic therapy ,Surgery ,Breast cancer ,Trastuzumab ,Internal medicine ,medicine ,In patient ,business ,medicine.drug - Abstract
1012 Background: CNS disease is a major problem among pts treated with H for stage IV HER2+ breast cancer with a reported incidence of 28–43%. This study was designed to characterize further the activity reported with lapatinib in an initial phase II trial in women with HER2+ disease metastatic to brain (Lin et al ASCO ‘06). Methods: Eligible pts had HER2+ breast cancer, prior H therapy and cranial RT, ECOG PS 0–2, and radiographic evidence of progressive brain metastases with at least one measurable (LD = 10mm) brain lesion. Pts received lapatinib 750 mg PO BID. Brain MRIs were obtained at 3.0 mm slices without gaps in the axial dimension. The primary endpoint was CNS response as defined by a = 50% volumetric (vol) reduction of CNS lesions in the absence of: new lesions, need for increased dose of steroids, progressive neurological signs/symptoms (NSS), or progressive extra-CNS disease. CNS disease progression was defined as either a = 40% vol increase from nadir, increase in steroid requirements, or progression of NSS. Results: The study exceeded its accrual goal of 220 pts in < 1 year; 238 pts were enrolled from Jan-Nov 06. Preliminary data from the initial 104 pts have undergone independent radiology review. 8 pts (7.7%) met vol criteria for partial response with a median absolute vol reduction of CNS disease of 3.6 cm3 (range 0.4 to 29.7 cm3). Exploratory analysis revealed that 17 of the initial 104 pts (16.3%) experienced a = 20% vol reduction of CNS disease with a median absolute vol reduction of 3.3cm3. The median time to vol progression in these 17 pts was 16 wks (range 12 -24 wks). Analysis of efficacy and tolerability based upon protocol defined criteria from all 238 pts will be presented. Conclusions: Preliminary data from this large multicenter trial provides evidence that lapatinib has activity based on vol reductions in pts with progressive HER2+ CNS disease following prior H-based systemic therapy and cranial RT. Definitive conclusions will be based on the entire database. Additional studies are warranted incorporating lapatinib in combination with other therapies and/or in a less refractory setting to optimize its use in HER2+ CNS disease. [Table: see text]
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- 2007
463. Relationship between glutathione-S-transferase P1 Ile105Val polymorphism and docetaxel neurosensory toxicity
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François Goldwasser, F. Rabillon, Jean-Marc Tréluyer, Olivier Mir, Véronique Girre, Jérôme Alexandre, Agnès Tran, G. Pons, and Véronique Diéras
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Cancer Research ,biology ,business.industry ,Pharmacology ,medicine.disease_cause ,Glutathione S-transferase ,Oncology ,Docetaxel ,Toxicity ,medicine ,biology.protein ,business ,Oxidative stress ,medicine.drug - Abstract
2527 Background: Glutathione-S-transferases (GST) regulate the cellular response to oxidative stress and various anticancer agents. We recently underlined the importance of oxidative stress in the side effects of taxanes [Alexandre et al,J Natl Cancer Inst 2006;98:236–44], and investigated the relationship between the GST isoforms M1, T1 and P1 genes polymorphisms and docetaxel-induced peripheral neuropathy. Methods: We retrospectively analysed GST polymorphisms in a cohort of cancer patients (pts) treated with docetaxel and entered in a clinical trial database. A clinical neurologic evaluation (according to the NCI-CTC v2.0) was performed at baseline and at each treatment cycle. The GST M1 (null genotype), GST T1 (null genotype), and GST P1 (Ile105Val and Ala114Val) polymorphisms were determined using PCR, followed by either sequencing or RFLP techniques. The relationship between GST polymorphisms and grade = 2 neurosenrory toxicity (NST) as primary endpoint was studied, using the Chi2-square (with Yates correction) and the Fischer’s two-tailed exact test. Results: Fifty-eight pts were included : F/M: 29/29; median age: 61 years (range: 47–75). Primary tumor: 27.6% breast, 27.6% prostate, 24.1% lung and 20.7% other cancers. Pts received docetaxel 75–100 mg/m2 given as single-agent. A total of 261 cycles were administered (median/pt: 4, range 2–12). Ten pts developed grade = 2 NST. Twenty-seven pts (47%) were homozygous for the GST P1 105Ile allele, and 31 pts were either homozygous or heterozygous for the GST P1 105Val allele. Grade = 2 NST was significantly more common in pts with GST P1 105Ile/105Ile genotype (8/27 pts, 30%) compared with patients with 105Ile/105Val or 105Val/105Val GSTP1 genotype (2/31 pts, 6,5%; P = 0.047). Pts who were genotyped as GST P1 105Ile/105Ile had a higher risk of developing a grade = 2 NST than did those with other GSTP1 genotypes (OR 6.11; 95% CI, 1.17–31.94; P < 0.05). Conclusions: We found a significant correlation between GST P1 105Ile homozygous genotype and the development of a docetaxel-induced peripheral neuropathy. No significant financial relationships to disclose.
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- 2007
464. Population pharmacokinetics of docetaxel in elderly patients
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Véronique Girre, S. Uriens, Véronique Diéras, Keyvan Rezai, and François Lokiec
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Renal function ,Population pharmacokinetics ,Pharmacology ,Docetaxel ,Pharmacokinetics ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
13020 Background: Elderly patients (>70 years) may present different pharmacokinetic profile for many drugs , mainly because of altered elimination due to renal function or metabolic decreases. Methods: Docetaxel, 50 to 85 mg/m2, median 70 mg/m2, was infused during 1 hr to 44 patients, aged 70 to 83 years, median 76.5 years. Three blood samples per patient were obtained according to a limited sampling strategy (Baille et al. Clin Cancer Res 1997, vol. 3, 1535–38). Covariates of interest were carefully recorded, age, body weight, body surface area, gender, serum creatinine, orosomucoid, serum albumin. These data were then analysed using NONMEM V to a) obtain individual Bayesian estimates of docetaxel clearance, b) re-analyse the data in order to estimate population parameters for this elderly population, c) show possible covariate effects on the pharmacokinetic parameters. Results: Median docetaxel CL from Bayesian estimation was 29.1 (2.5–97.5% quantiles 12–49) L/h. When the population was re-analysed per se, docetaxel CL was 29.2 (2.5–97.5% quantiles 17–35) L/h. The inter- subject variability for CL was 25% (precision 32%).. No covariate effect was observed on CL. Conclusions: Docetaxel clearance in elderly patients is slightly decreased, 29 L/h versus 36.8 L/h (reported in 547 patients, mean age 56 years, 5–95% quantiles 39–71 years). The inter-subject-variability of CL in elderly patients was decreased to 25% versus 47.5% in the 547 patients population. A pharmacokinetic- pharmacodynamic modelling of neutrophil counts versus time will be performed in these elderly patients in order to point a possible different sensitivity of this population to the myelosuppressive effects of docetaxel. No significant financial relationships to disclose.
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- 2007
465. 15 Use of a geriatric assessment questionnaire for older patients in an oncology clinic. Descriptive study of 105 patients at the Institut Curie, a French cancer treatment center
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M. Gisselbrecht, Carole Bouleuc, J-Y Pierga, F. Laki, Véronique Mosseri, R. Poinsot, Laurent Mignot, Véronique Diéras, G. Gridel, L. Ollivier, and Véronique Girre
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medicine.medical_specialty ,business.industry ,Oncology clinic ,Geriatric assessment ,Hematology ,Cancer treatment ,Oncology ,Older patients ,Physical therapy ,medicine ,Curie ,Center (algebra and category theory) ,Descriptive research ,business - Published
- 2006
466. Long median survival with capecitabine (X) single-agent therapy for patients (pts) with anthracycline- and taxane-pretreated metastatic breast cancer (MBC)
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Daniel Serin, Thierry Lesimple, Bruno Audhuy, P. Fumoleau, Rémy Largillier, Stéphane Culine, Véronique Diéras, L. Bobadilla, H. Orfeuvre, and C. Clippe
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Oncology ,Cancer Research ,medicine.medical_specialty ,Taxane ,Anthracycline ,business.industry ,medicine.disease ,Metastatic breast cancer ,Surgery ,Capecitabine ,Safety profile ,Internal medicine ,medicine ,High activity ,Single agent ,business ,Median survival ,medicine.drug - Abstract
10710 Background: X (Xeloda) is an oral fluoropyrmidine with consistently high activity in MBC, a good safety profile with little myelosuppression and no alopecia, and the convenience of oral administration. The addition of X to docetaxel in anthracycline-pretreated pts also increases survival. This non-randomized phase II study was conducted to evaluate the efficacy, safety and impact on quality of life (QoL) of X in pts with MBC pretreated with anthracyclines and taxanes. Main findings from this trial have been published previously [Fumoleau et al. Eur J Cancer 2004;40:536–42]. Here we present mature data after a follow-up of 48 months. Methods: Pts with anthracycline- and taxane-pretreated MBC received X 1250 mg/m2 twice daily on days 1–14 every 3 weeks for a median of 6 cycles (range 1–15). Results: Baseline characteristics of the 126 pts enrolled were typical of a pretreated MBC population. X achieved complete/partial response or stable disease in 63% of patients (overall response rate, 28%). Median time to progression was 4.9 months (95% CI: 4.0–6.4).Median duration of response was 5.9 months (95% CI: 4.5–12.7). The only grade 3/4 events occurring in ≥ 10% of patients were diarrhea (10%) and HFS (21%). The most common grade 3/4 laboratory abnormality was granulocytopenia (14%). After a follow-up of 48 months, 8 patients are still alive. Updated median overall survival is 15.9 months (95% CI: 13.5–21.3). 1-, 2- and 3-year survival rates are 63%, 37% and 17%, respectively. QoL assessment showed that X treatment was associated with an increase in mean Global Health Score up to cycle 6, with the increase maintained at subsequent evaluations. Conclusions: X is highly active in patients with anthracycline- and taxane-pretreated MBC, leading to a long median survival of 15.9 months. X is also well tolerated and improves QoL. [Table: see text]
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- 2006
467. Circulating tumor cells (CTCs) detection in a randomized phase II trial of neoadjuvant chemotherapy for large operable and locally advanced breast cancer (REMAGUS 02): Preliminary results
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Claire Mathiot, J-Y Pierga, P. Tresca, Véronique Diéras, Michel Marty, E. Brain, Laurent Mignot, J.M. Extra, J. Asselah, and Brigitte Sigal-Zafrani
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Locally advanced ,medicine.disease ,Metastatic breast cancer ,Breast cancer ,Circulating tumor cell ,Internal medicine ,medicine ,First line chemotherapy ,business - Abstract
10637 Background: The presence of CTCs in blood from metastatic breast cancer patients before first line chemotherapy and persistence of CTCs after initiation of treatment, are predictive of shorter overall survival (Cristofanilli M; et al, 2005, J Clin Oncol 23:1420–1430). CTCs could be used as a surrogate marker. The aim of this study was to determine if CTC were present in the blood of patients who received neoadjuvant chemotherapy (CT) for large operable and locally advanced breast cancer, before initiation of CT (preCT) and at the end of CT before surgery (postCT). Methods: 7.5 ml of blood were obtained on CellSave tube from patients included in an ongoing randomized phase II trial. All patients received 4 cycles of Epirubicin-Cyclophosphamide every 3 weeks followed by 4 cycles of docetaxel associated with or not trastuzumab for HER2 positive patients and with or not celecoxib for HER2 negative patients. CTCs were immunomagnetically separated and fluorescently stained with the CellSearch kit. Cells were classified using the CellSpotter Analyzer as CTCs if they stained positive for DAPI (nuclear dye), and cytokeratin 8, 18 and 19, and if they stained negative for the leucocyte-specific antibody CD45. Results: From 10/2004 to 12/2005, preCT blood samples were obtained in 60 patients, analyzed in 56 for technical reasons. At least one CTC was detected in 15/56 (27%, CI 95%: 15.5–38.5%), 1 to 17 cells per sample (median 1.5). With a threshold of 2 cells, 8/56 (14%, CI 95%: 5–23%) patients were classified positive. At time of analysis, pre CT and post CT samples from the same patient were available for 19 patients. Six had >1 CTC/sample before CT (31.5%) and only one (1/6, 17%) remained positive after CT. Thirteen were negative for CTC before CT and 2/13 (15%) became positive after CT, with only one cell per sample. Conclusions: CTCs can be detected in blood of patients with large operable or locally advanced breast cancer before initiation of neoadjuvant CT and can be monitored during treatment. Longer follow-up and a larger number of patients are expected before correlating these data with tumor response and survival. No significant financial relationships to disclose.
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- 2006
468. The financial impact of trastuzumab in metastatic breast cancer: The experience of the Institut Curie
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C. Le Tourneau, Catherine Buron, Marie-Noëlle Guilhaume, M. A. Doz, M. Courbard, Anne Vincent-Salomon, Alain Livartowski, B. Le Vu, and Véronique Diéras
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Financial impact ,Public health ,medicine.medical_treatment ,medicine.disease ,Metastatic breast cancer ,Targeted therapy ,Trastuzumab ,Internal medicine ,medicine ,Curie ,skin and connective tissue diseases ,business ,neoplasms ,medicine.drug - Abstract
663 Purpose: To estimate, in term of public health on the scale of a region, the cost of trastuzumab and to point out the financial impact of this new targeted therapy in the adjuvant setting. Methods: To understand the consequences of the spending on of trastuzumab at a macroeconomic level in the French hospital financing system, we decided to focus on an establishment in particular, and to analyze the increasing spending of trastuzumab at a micro-economic level, to provide a cost analysis of patients treated with trastuzumab for HER2-overexpressing metastatic breast cancer. We retrospectively reviewed 137 medical reports of patients who received trastuzumab either in combination with chemotherapy or as a single agent and in maintenance therapy. Median age of the patients was 52 years (range 32- to 79+). Eighty five percent had 3+ HER2 overexpression and fifteen percent had 2+ HER2 (FISH amplified). Results: Median survival from first treatment with trastuzumab was 38.5 months (range 0,04–53,06+). The cost of the first year treatment is in average €43,435.58 per patient, for the second year €36,419.01 and for the third year €37,198.94. Drugs cost represents 78% of the hospital stays cost for a patient and 2.9% of the budget of Institut Curie. Conclusions: This retrospective analysis showed the very high level of expenses of trastuzumab to treat metastatic breast cancers. With the adjuvant use of trastuzumab, it is expected that these expenses are going to increase exponentially. No significant financial relationships to disclose.
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- 2006
469. Prospective study of predictive factors of docetaxel (DCX)-induced febrile neutropenia (FN): Relevance of in vivo cytochrome 3A (CYP3A) phenotyping
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Vincent Montheil, G. Pons, Véronique Diéras, François Goldwasser, Jean-Marc Tréluyer, F. Rabillon, Sophie Grabar, Jérôme Alexandre, Agnès Tran, and E. Rey
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Oncology ,Cancer Research ,medicine.medical_specialty ,Cytochrome ,biology ,business.industry ,CYP3A ,medicine.disease ,Docetaxel ,In vivo ,Internal medicine ,Immunology ,biology.protein ,Medicine ,business ,Prospective cohort study ,Febrile neutropenia ,medicine.drug - Abstract
2046 Background: FN is a rare but severe side effect of DCX, remaining unpredictable. DCX is metabolised by CYP3A which displays high inter-individual variability. We studied the respective role of...
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- 2005
470. Docetaxel in elderly patients: Phase I and pharmacokinetic study
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J-Y Pierga, Véronique Diéras, Sophie Piperno-Neumann, P. Beuzeboc, V. Laurence, François Lokiec, Pierre Pouillart, Alain Livartowski, Véronique Girre, and M.-N. Guilhaume
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Oncology ,Cancer Research ,Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Clinical trial ,Pharmacokinetics ,Docetaxel ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
2113 Background: Elderly patients (>70 years) receive chemotherapy less frequently than younger and usually are excluded from clinical trials. The taxanes are among the most active agents available...
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- 2005
471. Dose-intensified chemotherapy and additional Docetaxel may improve inflammatory breast cancer patients outcome over two decades: Results from Institut Curie protocols 1977–1987 and two consecutive French multicenter trials Pegase 02 (1995–96) and Pegase 05 (1997–99)
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Bernard Asselain, Thierry Dorval, Véronique Mosseri, Thao Palangie, Véronique Diéras, J-Y Pierga, Pierre Pouillart, H. Roche, P. Beuzeboc, and Patrice Viens
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Anthracycline ,business.industry ,medicine.medical_treatment ,Improved survival ,medicine.disease ,Inflammatory breast cancer ,Surgery ,High dose chemotherapy ,Docetaxel ,Internal medicine ,Multicenter trial ,medicine ,business ,Median survival ,medicine.drug - Abstract
848 Background: Standard anthracycline based chemotherapy had improved survival of inflammatory breast cancer. New modalities have been developed over the past 10 years including sequential high dose chemotherapy and newer drugs such as taxanes. Methods: We analyzed a first (G1) of patients uniformly treated with conventional chemotherapy in our institution and compared to a second group (G2) receiving sequential HDC and a third group (G3) with HDC + docetacel G1: 223 pts (1977–1987) were treated at the Institut Curie on 3 consecutive protocoles with conventional doxorubicine based CT G2: 95 pts (1995–96) were enrolled onto the multicenter trial Pegase 02 consisting in four 3 weekly cycles of doxorubicine 75mg/m2 associated with CPM (6g/m2 at C1; 3g/m2 atC2) and 5FU 3g/m2 at C3 and C4 G3: 54 pts (1997–99) accrued in Pegase 05 multicenter trial received four 3 weekly cycles of D75mg/m2 + CPM 6g/m2 at C1; CPM 3g/m2 at C2, C6 and C7; docetaxel 100mg/m2 q 2W was administred at C3, C4 and C5 Median survival 3 ...
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- 2004
472. 935 A phase I study of the combination of docetaxel (D) and adriamicin (AD) in first line CT treatment of metastatic breast cancer (MBC)
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Pierre Pouillart, M. Gentin, N. Azli, Esteban Cvitkovic, J.L. Misset, Véronique Diéras, A. Riva, and G. Gruia
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Cancer Research ,medicine.medical_specialty ,Ejection fraction ,Anthracycline ,business.industry ,Urology ,Neutropenia ,medicine.disease ,Metastatic breast cancer ,Bolus (medicine) ,Oncology ,Docetaxel ,medicine ,Mucositis ,Premedication ,Nuclear medicine ,business ,medicine.drug - Abstract
The combination of D and AD is a logical attempt to optimize MBC therapy. The ongoing phase I trial has the objective to determine the DLT, MTD and RD in previously untreated pts with CT for MBC with measurable and/or eval disease receiving AD IV bolus followed by D 1 h IV infusion q3w. Prior Adjuvant CT with anthracycline (less than 300 mg/m2) was allowed provided at least a ≥ 12 month interval before study entry. Pts were required to have normal baseline LVEF monitored every 2 cycles. Prophylactic premedication is given with 3d. steroids (starting from d-18 mg every 6 hours) and Tanakan® from the day of 1st infusion. At least 3 pts are entered by dose level. The main toxicities are as follows: D/AD mg/m2 Pts(cy) Ent/Ev Neutropenta Mucositis Pts Feb Neutro Pts DLT Pts G4 G4 m. G1 G2 G3 Pts (cy) dur.(range) 50/40 3/3 (18) 1 (2) 3 (3–3) d 1 1 0 0 0/3 60/40 8/8 (39) 8 (36) 5 (2–10) d 6 1 0 3 2/8 60/50 8/4 (10) 4 (10) 6 (3–8) d 4 0 0 2 0/4 75/50 7/0 too early Except short lasting grade IV neutropenia, no grade 3–4 non hematological toxicity was observed. No CHF nor LVEF drop outside normal limits was observed. The toxicity data allow protocol continuation at dose level IV. As of March 95, there are 26 pts included (50% received prior anthracyclines). 16 pts are evaluable for response: 7 PR (5 mess. + 2 eval.), 2 CR (l eval), 6 NC (3 still ongoing) and one Po. PK profile of D, done in all pts will be available in this ongoing study. This combination is feasible, well tolerated and seems very active in MBC.
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- 1995
473. Phase II study of cystemustine in advanced eenal cancer
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M.A. Lentz, P. Kerbrat, Eric Pujade-Lauraine, P. Fargeot, J.C. Madelmont, Ph. Chollet, C. Toulouse, B. Chevallier, Chauvergne J, Véronique Diéras, and Antoine Adenis
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Cystemustine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Internal medicine ,Medicine ,Phases of clinical research ,Cancer ,business ,medicine.disease - Published
- 1995
474. Facteurs de risque et étude bactériologique d'une épidémie de diarrhée à Clostridium difficile dans un service d'oncologie adulte
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J-Y Pierga, Thao Palangie, M.-C Escande, Pouillart P, M. Jouve, Véronique Diéras, Véronique Girre, Thierry Dorval, C. Grandpeix, Bernard Asselain, F. Barbut, E. Blot, and Marie-Christine Falcou
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Gastroenterology ,Internal Medicine - Published
- 2000
475. Gemzar® (G) and epirubicin (E) in patients (pts) with metastatic breast cancer (MBC): Final results of a phase I dose finding study
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Marc Espié, Anne-Marie Rongier, P. Fumoleau, Eric Pujade-Lauraine, Pierre Pouillart, L. Kayitalire, Véronique Diéras, and Patrice Viens
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.disease ,Metastatic breast cancer ,Dose finding ,Internal medicine ,Medicine ,In patient ,business ,Epirubicin ,medicine.drug - Published
- 1999
476. Phase II study of sequential docetaxel (Taxotere®, TXT) and doxorubicin (Dox) as primary chemotherapy (CT) for large operable breast cancer (BC)
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J-Y Pierga, P. Beuzeboc, M. Jouve, Valérie Laurence, Véronique Girre, Véronique Diéras, Thao Palangie, J.M. Extra, J. Dorval, and Pierre Pouillart
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Phases of clinical research ,medicine.disease ,Breast cancer ,Docetaxel ,Internal medicine ,medicine ,Primary chemotherapy ,Doxorubicin ,business ,medicine.drug - Published
- 1999
477. Is ERBB-2 A predictive marker for response to primary chemotherapy for operable breast cancer: a prospective study in a phase ii randomized trial of doxorubicin/cyclophosphamide (AC) and doxorubicin/paclitaxel (AT)
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V. Le Doussal, Henri Magdelenat, F. Spyratos, Véronique Diéras, P. de Cremoux, J-Y Pierga, Anne Vincent-Salomon, Pierre Pouillart, and M. Tubiana-Hulin
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Oncology ,Cancer Research ,medicine.medical_specialty ,Predictive marker ,business.industry ,Doxorubicin/Cyclophosphamide ,medicine.disease ,law.invention ,Breast cancer ,Randomized controlled trial ,Doxorubicin/Paclitaxel ,ErbB ,law ,Internal medicine ,medicine ,Primary chemotherapy ,Prospective cohort study ,business - Published
- 1999
478. Cisplatin-docetaxel (Taxotere®) in first line treatment of advanced ovarian cancer (AOC)
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B. Weber, Eric Pujade-Lauraine, P. Winckel, Véronique Diéras, R. Kheder, D. Paraiso, J-M Ferrero, F. Mayer, and Alain Lortholary
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Oncology ,First line treatment ,Cancer Research ,medicine.medical_specialty ,Advanced ovarian cancer ,business.industry ,Internal medicine ,medicine ,Cisplatin/Docetaxel ,business - Published
- 1999
479. Timing of combined chemoradiotherapy in the conservative treatment of locally advanced breast cancer (LABC)
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Véronique Diéras, Alain Fourquet, P. Beuzebix, Thao Palangie, François Campana, B. Laguerre, Thierry Dorval, Suzy Scholl, J-Y Pierga, Pierre Pouillart, and Bernard Asselain
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Conservative treatment ,Oncology ,Cancer Research ,medicine.medical_specialty ,Breast cancer ,business.industry ,Internal medicine ,Locally advanced ,Medicine ,business ,medicine.disease ,Chemoradiotherapy - Published
- 1998
480. P64 Initial versus delayed radiotherapy combined with continuous 5-fluorouracile (F), cyclophosphamide (C) and doxorubicine (A) in inflammatory breast cancer (IBC)
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P. Beuzeboc, Thierry Dorval, Véronique Diéras, Suzy Scholl, Pierre Pouillart, Bernard Asselain, François Campana, M. Jouve, J-Y Pierga, and Thao Palangie
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Oncology ,Cancer Research ,medicine.medical_specialty ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,medicine.disease ,Inflammatory breast cancer ,Radiation therapy ,Internal medicine ,medicine ,business ,medicine.drug - Published
- 1998
481. P31 Prognostic significance of vascular tumor emboli in 1518 breast carcinoma patients with small tumor size (≤3 cm)
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Pierre Pouillart, J-Y Pierga, Anne Vincent-Salomon, Bernard Asselain, Xavier Sastre-Garau, M. Cousineau, Brigitte Zafrani, and Véronique Diéras
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Oncology ,Cancer Research ,medicine.medical_specialty ,Tumor size ,business.industry ,Internal medicine ,medicine ,Vascular tumor ,Radiology ,Breast carcinoma ,business - Published
- 1998
482. Response to chemotherapy is the first prognostic factor in metastatic breast cancer
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M. Jouve, J-Y Pierga, P. Beuzaboc, Garcia-Giralt E, Bernard Asselain, Pierre Pouillart, Véronique Diéras, Suzy Scholl, Thierry Dorval, and T. Patangié
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Oncology ,CA15-3 ,Cancer Research ,Chemotherapy ,medicine.medical_specialty ,Prognostic factor ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Metastatic breast cancer ,Breast cancer ,Internal medicine ,medicine ,business - Published
- 1997
483. Concurrent capecitabine and whole-brain radiotherapy for treatment of brain metastases in breast cancer patients.
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Cyrus Chargari, Youlia Kirova, Véronique Diéras, Pablo Pena, Francois Campana, Paul Cottu, JeanYves Pierga, and Alain Fourquet
- Abstract
Abstract Preclinical data have demonstrated that ionizing radiation acts synergistically with capecitabine. This report retrospectively assessed the use of capecitabine concurrently with whole-brain radiotherapy (WBRT) in patients with brain metastases from breast cancer. From January 2003 to March 2005, five breast cancer patients with brain metastases were referred for WBRT with concurrent capecitabine. Median age was 44 years (range: 38–53). The median dose of capecitabine was 1,000 mg/m2 twice daily for 14 days (day1–14). Treatment cycles were repeated every 21 days, concurrently with WBRT (30 Gy, 3 Gy per fraction, 5 days per week). Median survival after starting WBRT plus capecitabine was 6.5 months (range 1–34 months). One patient achieved a complete response. Two patients achieved partial response, including one with local control lasting until most recent follow-up. One patient had stable disease. The remaining patient was not assessable for response because of early death. Most commonly reported adverse events were nausea (n = 2) and headache (n = 2), always grade 1. Other toxicities were grade 3 hand/foot syndrome (n = 1), moderate anemia requiring transfusion and dose reduction of capecitabine (n = 1), and grade 1 mucositis (n = 1). Although promising, these preliminary data warrant further assessment of capecitabine-based chemoradiation in brain metastases from breast cancer and need to be further validated in the setting of a clinical trial. [ABSTRACT FROM AUTHOR]
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- 2009
484. 507 A phase II study of taxol® (T) (paclitaxel) over 3 hours (H) in 192 platinum pretreated patients (PTS) for ovarian carcinoma (OC)
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Thomas Bachelot, F. Oberling, M. Chazard, M. Schreinerova, I. Pruvot, P. Vennin, J.P. Guastalla, J-M Ferrero, Pierre Pouillart, F. Garat, Moïse Namer, M.A. Chanez, P. Kerbrat, B. Pellae-Cosset, P. Dufour, Pierre Fumoleau, P Soler-Michel, Catherine Lhommé, J.F. Héron, N. Tubiana, J. Fleury, Roland Bugat, Véronique Diéras, and Jacques Dauplat
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Cancer Research ,medicine.medical_specialty ,Nausea ,Anemia ,business.industry ,Phases of clinical research ,Evaluable Disease ,Neutropenia ,medicine.disease ,Gastroenterology ,Surgery ,Oncology ,Internal medicine ,Toxicity ,medicine ,Vomiting ,Mucositis ,medicine.symptom ,business - Abstract
Eligibility criteria histologically proven OC, measurable/evaluable disease, relapse/progression after at least one platinum based CT, ≤ 3 prior CT. Treatment 1 or 2 prior CT, T = 175 mg/m2 [Group A (A) = 151 pts]; 3 prior CT, T = 135 mg/m2 [Group B (B) = 41 pts] both by 3 hour IV infusion q 3 w. pts(192): median (med) age: 57 yrs (25–72); PS 0 = 74 pts, PS 1 = 88 pts, PS 2 = 34 pts. nb prior CT: 1 = 81 pts, 2 = 73 pts, 3 = 36 pts. Toxicity (% cycles): 1184 evaluable cycles (cy) (983 in A, 201 in B) with a med nb per pt of 6 in A (1–21), 5 in B (1–11). Cardiac tox.: bradycardia: (≤ 60 bpm) always asymptomatic = 13% (63 pts), hypotension (≤ 90 mm/Hg) = 3% (24 pts), drop in systolic blood pressure 30 mm/Hg = 3% (23 pts). Out of 841 cy EKG 3% were abnormal (13 pts). Minor hypersensitivity reactions (HSR): 18% (A = 19%, B = 9%) in 73 pts, flushing (12%) and skin rash (4%). In 80 cy (7%) symptomatic treatment was required but never T discontinuation. No severe HSR occurred. Hematologic tox. induced treatment delay in 4% (A = 3%, B = 6%) and dose reduction in 1%. Gr 3–4 neutropenia: A = 32%; B = 22%. Eleven pts experienced in 18 cy. any degree off ever of infection associated with a Gr 4 neutropenia, all in A. Thrombocytopenia Gr 3–4 = 1% (10 cy). Anemia Gr 3–4 = 3%, Creatininemia Gr 3 = 1 pt. Liver Tox. = 11 pts (6 with liver metastasis): ALP Gr 3–4 = 1%; ASAT Gr 3 = 0.3%. Nausea/vomiting Gr 1–2 = 13%.; Gr 3 = 2 cy. Mucositis Gr 1–2 = 4% all in A. Paresthesias (present in 45 pts at inclusion) Gr 1–2: A = 43%, B = 28%, Gr 3: A = 5 cy. Myalgias/arthralgias Gr 1–2 =18% (A = 20%, B = 7%) and Gr 3 in 3 cy. Fatique Gr 1–2 = 26%. Edema Gr. 1–2 = 6% and Gr 3 in I cy. No toxic death occurred. Efficacy 185 evaluable pts, RR = 20% (CR = 5%, PR = 15%), SO = 32% (3 pts pCR) Conclusion Taxol® given by 3 H infusion, is well tolerated. The RR seems not different from those observed with 24 H infusion.
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- 1995
485. Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers.
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Paul H Cottu, Jacques Bonneterre, Andrea Varga, Mario Campone, Alexandra Leary, Anne Floquet, Dominique Berton-Rigaud, Marie-Paule Sablin, Anne Lesoin, Keyvan Rezai, François M Lokiec, Catherine Lhomme, Jacques Bosq, Alice S Bexon, Erard M Gilles, Stefan Proniuk, Veronique Dieras, David M Jackson, Alexander Zukiwski, and Antoine Italiano
- Subjects
Medicine ,Science - Abstract
INTRODUCTION:Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker. METHODS:An open-label, multicenter, randomized, parallel-group, phase 1 study (target n = 60; NCT02052128) included female patients ≥18 years with PRpos tumors. APR analysis was performed on archival tumor tissue. Patients were randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint was to identify the recommended phase 2 dose. Secondary endpoints included safety, clinical benefit and pharmacokinetics. RESULTS:The phase 1 dose escalation component of the study is complete (n = 52). Tumor diagnosis included: endometrial carcinoma 12; breast cancer 20; ovarian cancer 13; other 7. Median age was 64 (36-84). No dose limiting toxicity was observed with reported liver function test elevation related only to liver metastases. The RP2D was 50 mg ER BID. Median therapy duration was 8 weeks (range 2-44), and 9 patients had clinical benefit ≥24 weeks, including 2 patients with APRpos endometrial carcinoma. CONCLUSION:Clinical benefit with excellent tolerance was seen in heavily pretreated patients with endometrial, ovarian and breast cancer. The data support the development of Onapristone in endometrial endometrioid cancer. Onapristone should also be evaluated in ovarian and breast cancers along with APR immunohistochemistry validation.
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- 2018
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486. Safety and immunogenicity of neoadjuvant treatment using WT1-immunotherapeutic in combination with standard therapy in patients with WT1-positive Stage II/III breast cancer: a randomized Phase I study
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G. Kunz, Peter A. Fasching, Steve Chan, P. Krivorotko, M. Higgins, A. Ferro, F. F. Lehmann, Sherko Kuemmel, Giuseppe Curigliano, P. M. De Sousa Alves, Lee S. Schwartzberg, Mario Campone, Thomas Bachelot, Marc Gillet, Paul E. Goss, V. Wascotte, and Véronique Diéras
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Cancer Research ,medicine.medical_treatment ,Medizin ,Breast Neoplasms ,Placebo ,Cancer Vaccines ,Antibodies ,law.invention ,03 medical and health sciences ,Breast cancer ,0302 clinical medicine ,Randomized controlled trial ,Antigens, Neoplasm ,law ,WT1 antigen ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Combined Modality Therapy ,WT1 Proteins ,Adverse effect ,Neoadjuvant therapy ,Neoplasm Staging ,Chemotherapy ,business.industry ,medicine.disease ,Clinical Trial ,Immunogenicity ,Neoadjuvant Therapy ,Recombinant Proteins ,Treatment Outcome ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,Female ,Immunotherapy ,Safety ,business - Abstract
Purpose This Phase I, multicenter, randomized study (ClinicalTrials.gov NCT01220128) evaluated the safety and immunogenicity of recombinant Wilms’ tumor 1 (WT1) protein combined with the immunostimulant AS15 (WT1-immunotherapeutic) as neoadjuvant therapy administered concurrently with standard treatments in WT1-positive breast cancer patients. Methods Patients were treated in 4 cohorts according to neoadjuvant treatment (A: post-menopausal, hormone receptor [HR]-positive patients receiving aromatase inhibitors; B: patients receiving chemotherapy; C: HER2-overexpressing patients on trastuzumab–chemotherapy combination; D: HR-positive/HER2-negative patients on chemotherapy). Patients (cohorts A–C) were randomized (2:1) to receive 6 or 8 doses of WT1-immunotherapeutic or placebo together with standard neoadjuvant treatment in a double-blind manner; cohort D patients received WT1-immunotherapeutic in an open manner. Safety was assessed throughout the study. WT1-specific antibodies were assessed pre- and post-vaccination. Results Sixty-two patients were randomized; 60 received ≥ one dose of WT1-immunotherapeutic. Two severe toxicities were reported: diarrhea (cohort C; also reported as a grade 3 serious adverse event) and decreased left ventricular ejection fraction (cohort B; also reported as a grade 2 adverse event). Post-dose 4 of WT1-immunotherapeutic, 10/10 patients from cohort A, 0/8 patients from cohort B, 6/11 patients from cohort C, and 2/3 patients from cohort D were humoral responders. The sponsor elected to close the trial prematurely. Conclusions Concurrent administration of WT1-immunotherapeutic and standard neoadjuvant therapy was well tolerated and induced WT1-specific antibodies in patients receiving neoadjuvant aromatase inhibitors. In patients on neoadjuvant chemotherapy or trastuzumab–chemotherapy combination, the humoral response was impaired or blunted, likely due to either co-administration of corticosteroids and/or the chemotherapies themselves. Electronic supplementary material The online version of this article (doi:10.1007/s10549-017-4130-y) contains supplementary material, which is available to authorized users.
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487. New advances in DPYD genotype and risk of severe toxicity under capecitabine.
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Marie-Christine Etienne-Grimaldi, Jean-Christophe Boyer, Christophe Beroud, Litaty Mbatchi, André van Kuilenburg, Christine Bobin-Dubigeon, Fabienne Thomas, Etienne Chatelut, Jean-Louis Merlin, Frédéric Pinguet, Christophe Ferrand, Judith Meijer, Alexandre Evrard, Laurence Llorca, Gilles Romieu, Philippe Follana, Thomas Bachelot, Loic Chaigneau, Xavier Pivot, Véronique Dieras, Rémy Largillier, Mireille Mousseau, Anthony Goncalves, Henri Roché, Jacques Bonneterre, Véronique Servent, Nadine Dohollou, Yann Château, Emmanuel Chamorey, Jean-Pierre Desvignes, David Salgado, Jean-Marc Ferrero, and Gérard Milano
- Subjects
Medicine ,Science - Abstract
Deficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine.Two-hundred forty-three patients were analysed (88.5% capecitabine monotherapy). Grade 3 and grade 4 capecitabine-related digestive and/or neurologic and/or hemato-toxicities were observed in 10.3% and 2.1% of patients, respectively. DPYD exome, along with flanking intronic regions 3'UTR and 5'UTR, were sequenced on MiSeq Illumina. DPD phenotype was assessed by pre-treatment plasma uracil (U) and dihydrouracil (UH2) measurement.Among the 48 SNPs identified, 19 were located in coding regions, including 3 novel variations, each observed in a single patient (among which, F100L and A26T, both pathogenic in silico). Combined analysis of deleterious variants *2A, I560S (*13) and D949V showed significant association with grade 3-4 toxicity (sensitivity 16.7%, positive predictive value (PPV) 71.4%, relative risk (RR) 6.7, p16 ng/ml) did not substantially increase the sensitivity, while impairing PPV and RR.Exploring an extended set of deleterious DPYD variants improves the performance of DPYD genotyping for predicting both grade 3-4 and grade 4 toxicities (digestive and/or neurologic and/or hematotoxicities) related to capecitabine, as compared to conventional genotyping restricted to consensual variants *2A, *13 and D949V.
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- 2017
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488. P08.032B3-101, GLUTATHIONE PEGYLATED LIPOSOMAL DOXORUBICIN, IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS AND BREAST CANCER BRAIN METASTASES
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Hans Gelderblom, Philippe Aftimos, Sevilay Altintas, M. E. van Linde, Véronique Diéras, Monica Arnedos, Patricia M. M. B. Soetekouw, Agnes Jager, Carey K. Anders, and Dieta Brandsma
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Neutropenia ,medicine.disease ,Chemotherapy regimen ,Surgery ,Poster Presentations ,Tolerability ,Trastuzumab ,Response Evaluation Criteria in Solid Tumors ,Internal medicine ,Glioma ,Mucositis ,Medicine ,Neurology (clinical) ,business ,medicine.drug - Abstract
BACKGROUND: Without active delivery across the blood-brain barrier (BBB), efficacy of doxorubicin in intracranial tumors is limited. Glutathione pegylated liposomal doxorubicin (2B3-101) was developed as a brain-targeted chemotherapy. In rats treated with 2B3-101 doxorubicin brain delivery was 5-fold higher as compared to pegylated liposomal doxorubicin (Doxil®/Caelyx®). This resulted in a significant improvement in glioma growth inhibition. In a Phase I dose escalation study in 37 patients with advanced solid tumors and brain metastases (n = 24) or recurrent high grade gliomas (HGG; n = 13), 2B3-101 was well tolerated up to a dose intensity of 15 mg/m2/wk, both as single agent and in combination with trastuzumab. Preliminary evidence of anti-tumor activity was observed, including 1 intracranial partial response (PR) and 16 patients with stable disease (SD) after 2 cycles. These results warranted proceeding into a Phase IIa study. METHODS: The purpose of the ongoing Phase IIa study is to evaluate the safety, tolerability and intracranial anti-tumor activity of 2B3-101 in patients with recurrent HGG and the intracranial and extra-cranial anti-tumor activity of 2B3-101 in patients with breast cancer brain metastases (BCBM) (n = 14 per group). Patients with recurrent HGG are treated with 2B3-101 60 mg/m2 iv q28d while patients with BCBM are treated with 2B3-101 50 mg/m2 iv q21d, in HER2 positive patients combined with trastuzumab (iv, 6mg/kg, q21d). Results up to March 15th 2014 are described in this abstract; in October 2014 the complete data set will be presented. RESULTS: To date, 18 patients with HGG and 10 patients with BCBM have been enrolled in the Phase IIa part of the study and have received a total of 35 (range 1-4) and 34 (range 1-7) cycles of 2B3-101, respectively. At both dose regimes, the side effects were consistent with Doxil®/Caelyx® and with the earlier Phase I results of 2B3-101. The most common adverse events (AEs) grade ≥2 related to 2B3-101 were: neutropenia (28%), palmar-plantar erythrodysesthesia (PPE) (21%), infusion reactions (21%) and oral mucositis (17%). No CNS and/or cardiac toxicity were reported. 2B3-101 cycles were administered per protocol in 92% of the HGG patients and in 62% of the BCBM patients. The main reasons for dose delays/ reductions were neutropenia (19%) and PPE (69%). The anti-tumor activity was evaluable in 13 patients with HGG and in 9 patients with BCBM. In the HGG cohort, 31% of the patients had SD as best response (RANO), including 2 patients with a response of ≥30%. In the BCBM cohort, 11% had a PR and 56% had SD as best response (RECIST). The latter group, included 3 more patients with an intracranial response of ≥20%. CONCLUSIONS: This phase I/IIa trial shows that 2B3-101 has anti-tumor activity with a tolerable safety profile in recurrent HGG and in BCBM patients. These results warrant further randomized, controlled Phase IIb studies in both patient populations.
489. Long-term prognostic performance of Ki67 rate in early stage, pT1-pT2, pN0, invasive breast carcinoma.
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Fabien Reyal, David Hajage, Alexia Savignoni, Jean-Guillaume Feron, Marc Andrew Bollet, Youlia Kirova, Alain Fourquet, Jean-Yves Pierga, Paul Cottu, Veronique Dieras, Virginie Fourchotte, Fatima Laki, Severine Alran, Bernard Asselain, Anne Vincent-Salomon, Brigitte Sigal-Zafrani, and Xavier Sastre-Garau
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Medicine ,Science - Abstract
BACKGROUND: Molecular signatures may become of use in clinical practice to assess the prognosis of breast cancers. However, although international consensus conferences sustain the use of these new markers in the near future, concerns remain about their degree of discordance and cost-effectiveness in different international settings. The present study aims to validate Ki67 as prognostic factor in a large cohort of early-stage (pT1-pT2, pN0) breast cancer patients. METHODS: 456 patients treated in 1995-1996 were identified in the Institut Curie database. Ki67 (MIB1) was retrospectively assessed by immunohistochemistry for all cases. The prognostic value of this index was compared to that of histological grade (HG), Estrogen receptor (ER) and HER2 status. Distant disease free interval, loco-regional recurrence, time-lapse from first metastatic diagnosis to death were analyzed. RESULTS: All 456 patients were treated by lumpectomy plus axillary dissection and radiotherapy. 27 patients (5.9%) received systemic treatment. Tumors were classified as HG1 in 35%, HG2 in 42% and HG3 in 23% of cases. ER was expressed in 86% of the tumors, HER2 in 5% and 14% were triple negative. The median follow-up was 151 [5-191] months. Distant and loco-regional disease recurrences were observed in 16% and 18%, respectively. High (>20%) Ki67 rate [HR = 3 (1.8-4.8), p
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- 2013
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490. Respective prognostic value of genomic grade and histological proliferation markers in early stage (pN0) breast carcinoma.
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Fabien Reyal, Marc A Bollet, Martial Caly, David Gentien, Sabrina Carpentier, Hélène Peyro-Saint-Paul, Jean-Yves Pierga, Paul Cottu, Véronique Dieras, Brigitte Sigal-Zafrani, Anne Vincent-Salomon, and Xavier Sastre-Garau
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Medicine ,Science - Abstract
BackgroundGenomic grade (GG) is a 97-gene signature which improves the accuracy and prognostic value of histological grade (HG) in invasive breast carcinoma. Since most of the genes included in the GG are involved in cell proliferation, we performed a retrospective study to compare the prognostic value of GG, Mitotic Index and Ki67 score.MethodsA series of 163 consecutive breast cancers was retained (pT1-2, pN0, pM0, 10-yr follow-up). GG was computed using MapQuant Dx(R).ResultsGG was low (GG-1) in 48%, high (GG-3) in 31% and equivocal in 21% of cases. For HG-2 tumors, 50% were classified as GG-1, 18% as GG-3 whereas 31% remained equivocal. In a subgroup of 132 ER+/HER2- tumors GG was the most significant prognostic factor in multivariate Cox regression analysis adjusted for age and tumor size (HR = 5.23, p = 0.02).ConclusionsIn a reference comprehensive cancer center setting, compared to histological grade, GG added significant information on cell proliferation in breast cancers. In patients with HG-2 carcinoma, applying the GG to guide the treatment scheme could lead to a reduction in adjuvant therapy prescription. However, based on the results observed and considering (i) the relatively close prognostic values of GG and Ki67, (ii) the reclassification of about 30% of HG-2 tumors as Equivocal GG and (iii) the economical and technical requirements of the MapQuant micro-array GG test, the availability in the near future of a PCR-based Genomic Grade test with improved performances may lead to an introduction in clinical routine of this test for histological grade 2, ER positive, HER2 negative breast carcinoma.
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- 2012
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491. Correction: Respective Prognostic Value of Genomic Grade and Histological Proliferation Markers in Early Stage (pN0) Breast Carcinoma.
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Fabien Reyal, Marc A. Bollet, Martial Caly, David Gentien, Sabrina Carpentier, Hélène Peyro-Saint-Paul, Jean-Yves Pierga, Paul Cottu, Véronique Dieras, Brigitte Sigal-Zafrani, Anne Vincent-Salomon, and Xavier Sastre-Garau
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Medicine ,Science - Published
- 2012
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492. Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial.
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Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, Zujewski JA, Goldhirsch A, Armour A, Pritchard KI, McCullough AE, Dolci S, McFadden E, Holmes AP, Tonghua L, Eidtmann H, Dinh P, Di Cosimo S, Harbeck N, Tjulandin S, Im YH, Huang CS, Diéras V, Hillman DW, Wolff AC, Jackisch C, Lang I, Untch M, Smith I, Boyle F, Xu B, Gomez H, Suter T, Gelber RD, and Perez EA
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- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms chemistry, Breast Neoplasms pathology, Chemotherapy, Adjuvant, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Lapatinib, Middle Aged, Neoplasm Staging, Patient Selection, Treatment Outcome, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Biomarkers, Tumor analysis, Breast Neoplasms drug therapy, Quinazolines administration & dosage, Quinazolines adverse effects, Receptor, ErbB-2 analysis, Trastuzumab administration & dosage, Trastuzumab adverse effects
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Background: Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain., Methods: In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T., Results: Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms., Conclusion: Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care., (© 2015 by American Society of Clinical Oncology.)
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- 2016
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493. Trastuzumab emtansine in human epidermal growth factor receptor 2-positive metastatic breast cancer: an integrated safety analysis.
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Diéras V, Harbeck N, Budd GT, Greenson JK, Guardino AE, Samant M, Chernyukhin N, Smitt MC, and Krop IE
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- Ado-Trastuzumab Emtansine, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents adverse effects, Breast Neoplasms pathology, Female, Humans, Maytansine adverse effects, Maytansine therapeutic use, Middle Aged, Neoplasm Metastasis, Randomized Controlled Trials as Topic, Trastuzumab, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms enzymology, Maytansine analogs & derivatives, Receptor, ErbB-2 metabolism
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Purpose: The antibody-drug conjugate trastuzumab emtansine (T-DM1) combines the cytotoxic activity of DM1 with the human epidermal growth factor receptor 2 (HER2) -targeted, antitumor properties of trastuzumab. T-DM1 has shown activity in phase I and II single-arm studies in patients with pretreated HER2-positive metastatic breast cancer (MBC) and has demonstrated superior efficacy and improved tolerability versus standard MBC treatments in randomized phase II and III studies. This analysis, combining available data from all single-agent T-DM1 studies to date, was conducted to better define the T-DM1 safety profile., Patients and Methods: Six studies in patients with HER2-positive MBC who received T-DM1 3.6 mg/kg every 3 weeks and follow-up data from patients in an extension study were analyzed. Analyses included adverse events (AEs) by grade; AEs leading to death, drug discontinuation, or dose reduction; and select AEs., Results: Among 884 T-DM1-exposed patients, the most commonly reported all-grade AEs were fatigue (46.4%), nausea (43.0%), thrombocytopenia (32.2%), headache (29.4%), and constipation (26.5%). The most common grade 3 to 4 AEs were the laboratory abnormalities of thrombocytopenia (11.9%) and increased AST serum concentration (4.3%). These were manageable and not generally associated with clinical symptoms. There were 12 AE-related deaths. AEs resulted in dose reductions in 17.2% of patients and drug discontinuations in 7.0%., Conclusion: In this analysis of 884 T-DM1-exposed patients, grade 3 or greater AEs were infrequent and typically asymptomatic and manageable. This favorable safety profile makes T-DM1 treatment suitable for exploration in other breast cancer settings., (© 2014 by American Society of Clinical Oncology.)
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- 2014
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494. Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer.
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Miller KD, Diéras V, Harbeck N, Andre F, Mahtani RL, Gianni L, Albain KS, Crivellari D, Fang L, Michelson G, de Haas SL, and Burris HA
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- Ado-Trastuzumab Emtansine, Adult, Aged, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms genetics, Breast Neoplasms mortality, Disease-Free Survival, Female, Genes, erbB-2, Humans, Kaplan-Meier Estimate, Maytansine administration & dosage, Maytansine adverse effects, Middle Aged, Neoplasm Metastasis, Trastuzumab, Antibodies, Monoclonal, Humanized administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Breast Neoplasms drug therapy, Maytansine analogs & derivatives
- Abstract
Purpose: Our phase IIa study characterized the safety and efficacy of two human epidermal growth factor receptor 2 (HER2) -targeted agents, trastuzumab emtansine (T-DM1) and pertuzumab, in patients with HER2-positive metastatic breast cancer (MBC)., Patients and Methods: Patients with HER2-positive locally advanced breast cancer or MBC were treated with 3.6 mg/kg T-DM1 plus pertuzumab (840-mg loading dose, then 420 mg subsequently) once every 3 weeks. The primary efficacy end point was investigator-assessed objective response rate (ORR)., Results: Sixty-four patients (43 patients in the second-line or greater setting [advanced MBC]; 21 patients in the first-line setting [first-line MBC]) were enrolled. Patients with advanced MBC had received trastuzumab and a median of six prior nonhormonal treatments for MBC; 86% of first-line MBC patients had received trastuzumab in the (neo)adjuvant setting. The ORR was 41% overall, 33% in patients with advanced MBC, and 57% in first-line patients. Median progression-free survival was 6.6, 5.5, and 7.7 months, respectively. The most common adverse events were fatigue (61%), nausea (50%), and diarrhea (39%). The most frequent grade ≥ 3 adverse events were thrombocytopenia (13%), fatigue (11%), and liver enzyme elevations (increased ALT: 9%; increased AST: 9%). One patient had left ventricular ejection fraction of less than 40% after study drug discontinuation. Exploratory biomarker analyses demonstrated that patients with above-median tumor HER2 mRNA levels had a numerically higher ORR than patients with below-median levels (44% v 33%, respectively)., Conclusion: T-DM1 and pertuzumab can be combined at full doses with no unexpected toxicities. The preliminary efficacy in patients in the first-line and advanced MBC settings warrants further investigation.
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- 2014
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