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  • American Association for Cancer Research (AACR)  (10)
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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. GS2-07-GS2-07
    Abstract: Since 2005, 12 months of trastuzumab added to chemotherapy alone is the standard of care in patients with HER2-positive breast cancer. PHARE ('Protocol for Herceptin® as Adjuvant therapy with Reduced Exposure') is the first trial comparing a reduction of adjuvant trastuzumab versus the standard 12 months. In 2012, the first analysis failed to prove that 6-months was non-inferior to 12-months of adjuvant trastuzumab (NCT00381901). The current presentation reports the final analysis. Methods: The trial was sponsored by the French National Cancer Institute (INCa) (www.e-cancer.fr), and approved by central Ethical Committee on May 15th 2006. Patients with HER2-positive early breast cancer were randomly assigned between 12 and 6 months of adjuvant trastuzumab duration. The randomization was stratified by concomitant or sequential trastuzumab administration with chemotherapy, estrogen receptor (ER) status and center. The primary objective was non-inferiority of 6- versus 12-months arms in the intent to treat population, in terms of disease-free survival (DFS) with a pre-specified hazard margin of 1.15. Overall Survival (OS) and metastasis free survival (MFS) were secondary endpoints. Results: A total of 3380 patients were randomized, their median age was 54 years (21-86). Patients and disease characteristics were well balanced between the two arms. No involved axillary node was observed in 54.5% of cases, 41.7% of tumors were ER negative. At a median follow-up of 7.5 years, 704 events counting for DFS were observed. Between the 12- and 6-months arms, the adjusted Hazard Ratio (HR) for DFS rates was 1.08 (95%CI: 0.93-1.25; p=0.39) favoring the longer exposure. The 1.15 margin of non-inferiority was included in the 95%CI. No heterogeneity in terms of treatment effect was observed, no significant difference for trastuzumab duration effects was found in any subgroups.For OS and MFS, the adjusted HR were 1.13 (95%CI 0.92-1.39) and 1.15 (95%CI 0.96-1.37), respectively. Conclusion: The choice of the non-inferiority margin will remain inherently a subject of controversy especially in the context of oncology trials where the primary outcome is survival and the least additional death could be considered unacceptable questioning the very feasibility of such trials. Nevertheless, PHARE failed to show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. The standard of care should remain 12 months of adjuvant trastuzumab. Citation Format: Pivot X, Romieu G, Debled M, Pierga J-Y, Kerbrat P, Bachelot T, Espie M, Lortholary A, Fumoleau P, Serin D, Jacquin J-P, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Venat-Bouvet L, Cany L, Catala S, Khayat D, Gambotti L, Pauporte I, Faure Mercier C, Paget-Bailly S, Henriques J, Grouin J-M. PHARE randomized trial final results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS2-07.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 24_Supplement ( 2013-12-15), p. P4-01-05-P4-01-05
    Abstract: Objectives : A French multicenter study was promoted by the national French cancer federation (Unicancer R & D) to assess the potential of [18F]FLT (positron emission tomography (PET) biomarker of proliferation)to manage breast cancer neoadjuvant chemotherapy (NAC). The main objective was to compare changes in tumor [18F] FLT uptake to histopathological changes induced by NAC, assuming an arrest of tumor growth related to the effectiveness of NAC. Methods : 97 patients (age 48.6 +/- 10.2 y.) were included in 13 nuclear medicine centers. All patients were eligible to anthracycline-based NAC for a de novo unifocal breast cancer (ductal n = 84, lobular = 11, other type = 2; stage II n = 75, stage III n = 21 et stage IV n = 1). 90 patients underwent a baseline PET before the onset of NAC (PET1) and a final PET after the end of NAC and before surgery (PET3). PET acquisitions were performed 60±7min after FLT injection. SUVmax (maximum standardized uptake value), SUVpeak (1 cm3 ROI including pixel max) and SUV41 (isocontour 41% of pixel max) were computed. Changes in SUV on PET3 vs PET1 were analyzed in relation to histopathological findings at the end of NAC (Sataloff criteria). Results : Tumor FLT uptake decreased markedly between TEP1 and TEP3 (SUVmax = 6.2±4.8 vs 1.3±1.2 respectively; SUVpeak = 4.6±3.2 vs 0.9±0.9; SUV41 = 3.6±2.8 vs 0.8±0.7). Total or near-total therapeutic effect (grade A) were obtained in 20 patients, more than 50% therapeutic effect but less than total or near-total effect (grade B) in 37 patients, less than 50% therapeutic effect but visible effect (grade C) in 22 patients, or no therapeutic effect (grade D) in 11 patients. SUVmax decreased dramatically (87.5%) to background levels in all patients with a complete response (grade A). Overall, changes in SUV differed depending on the type of histological response (p & lt;0.01) i.e. SUVmax changes were more pronounced as pathological responses were good: 61% for grade D; 65.7% grade C and 69.8% grade B. The same results were obtained with the two other SUV types. Conclusions : Pathologic response to NAC in breast cancer can be assessed accurately by FLT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-05.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 4_Supplement ( 2016-02-15), p. P1-08-06-P1-08-06
    Abstract: Background: Due to better molecular classification and new treatment options, epidemiology and prognosis of mBC is rapidly changing. Clinical data extracted from randomized studies are only relevant to specific subpopulations and retrospective studies are prone to selection bias. SToRM is a prospective clinical trial that aims to create a cohort of 1500 mBC patients, with the ultimate goal of identifying germ line polymorphisms associated with prognosis of breast cancer (BC) and response to treatment in the metastatic phase. Material and methods: Any newly (within 1 year) diagnosed mBC patients were eligible. Whole blood samples were drawn and germline DNA extracted for genetic analysis. Extensive epidemiologic data, disease history from primary diagnosis to metastatic spread, pathological characteristics and ER, PR and HER2 status were collected. Patients are prospectively followed until death. Genotyping using the HumanCoreExome chipset from Illumina is currently underway and will be completed in early summer 2015. Results: 1502 patients were included from March 2012 to May 2014 from 71 French institutions. Median age at metastatic relapse was 60 years (range 26-93). Median time from primary diagnosis to metastatic relapse was 30 months (range 0-473) with 24% of patients already metastatic at initial diagnosis. 78% of patients were ER+, 18% were HER2+ and only 16% were triple negative. Molecular subtype classification derived from pathological data following St Gallen consensus recommendations is presented below:  n (%)Luminal A like261 (22.2%)Luminal B like HER2 negative476 (40.5%)Luminal B like HER2 positive134 (11.4%)HER2 positive non Luminal (ER-)111 (9.5%)Triple negative193 (16.4%)Missing data327 64% of the patients had received previous adjuvant treatment, among which 81% received adjuvant chemotherapy and 9% trastuzumab. At metastatic relapse, loco-regional progression, liver, lung and bone metastasis were documented in 301 (20%), 494 (33%), 410 (27%) and 1017 (68%) patients respectively. 313 patients (21%) had bone only metastatic disease. First line treatment included: chemotherapy (71%), endocrine therapy (50%) and anti-HER2 treatments (17%). Survival data will be presented at the meeting. Conclusion: Despite a theoretically better prognosis and widespread use of adjuvant hormonal treatment, ER+/HER2- breast cancer still account for more than 60% of mBC. The proportion of patients with HER2+ disease (18%) and triple negative disease (16%) is consistent with percentages observed in early BC populations. In comparison with a cohort of "cured", localized cancer, such as the SIGNAL/PHARE study, GWAS analysis will allow for the identification of genetic polymorphisms correlated with treatment resistance. Fundamentally, such variants will provide insight into the molecular mechanisms responsible for host-genetic influence on BC progression. From a clinical perspective, genetic variants that predispose to metastatic disease can serve as stratification variables in future clinical trials, particularly as the development of new treatment options for resistant BC is needed. Citation Format: Bachelot T, Lavergne E, Romieu G, Rios M, Heudel P-E, Roemer-Becuwe C, Jouannaud C, Tredan O, Chaigneau L, Arnedos M, Orfeuvre H, Petit T, Quenel-Tueux N, Jacquin J-P, Ferrero J-M, Moullet I, Abadie-Lacourtoisie S, Penault-Llorca F, Blanc E, Cox D. SToRM: A prospective clinical trial of 1502 metastatic breast cancer (mBC) patients with detail of clinical presentation, molecular subtype, treatment modalities, prognosis and GWAS genotyping. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-08-06.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 24_Supplement ( 2009-12-15), p. 3174-3174
    Abstract: Background: Since 2003, through the impetus given by Pr Erick Gamelin and the Regional Health Agency in Western France (Bretagne, Pays de Loire), a network called OMIT (Drugs and Emerging Therapeutics Observatory) has been created, including the Breast Cancer Forum. Anthracyclins and taxanes are the cornerstones of adjuvant chemotherapy for breast cancer. In France, since the PACS 01 publication1, FEC 100 followed by docetaxel 100 has been the standard adjuvant chemotherapy regimen in breast cancer. Long term toxicities like persistent alopecia or suboptimal hair regrowth have been observed.Methods: Over the last year, the first cases of persistent alopecia or suboptimal hair regrowth after adjuvant chemotherapy have been reported to the Breast Cancer Forum. Consequently, OMIT quickly drew up a case report form and mailed it to every oncologist in Western France to collect data.Results: From May 2008 to April 2009, 66 cases of persistent alopecia or suboptimal hair regrowth after adjuvant chemotherapy from 15 different institutions were declared to OMIT: median age: 60 years (35-78), hypothyroidia: 11, fine hair before treatment: 2. Alopecia was localized: 13, diffuse: 49, complete: 4. The time lapse between the end of chemotherapy and persisting alopecia has been more than 3 months: 5 patients, more than 6 months: 10, more than 12 months: 22, more than 24 months: 29. The chemotherapy regimens were various: schedule FEC (epirubicin 100 mg/msq), 3 courses followed by docetaxel 100 mg/msq, 3 courses: 54, docetaxel 100 mg/msq: 3, TCH (docetaxel-carboplatin-trastuzumab) or TH: 2, FEC 100: 2, epirubicin 75 mg/msq in association with docetaxel 75 mg/msq: 2. Hormonotherapy: letrozole: 13, anastrozole: 18, exemestane: 3, tamoxifene: 14, LH-RH agonist: 3. No hormonotherapy: 13. In some institutions, according to the ECOG trial2, some oncologists quickly decided to change their standard regimen from FEC 100 - docetaxel 100, to EC 100 4 courses followed by weekly paclitaxel for 12 weeks: forthcoming data on persistent alopecia, suboptimal hair regrowth or neuropathy after this ECOG adjuvant chemotherapy regimen will be presented at the symposium.Conclusion: For the first time in France, Western OMIT offers us data about persistent alopecia or suboptimal hair regrowth after adjuvant chemotherapy: it is an important side effect and must be considered by oncologists as optimal information to give to curable patients. The next step is to evaluate the real incidence of this phenomen on the population of patients treated by adjuvant chemotherapy for breast cancer: OMIT is currently working with the Federation Nationale des Centres de Lutte contre le Cancer (FNCLCC) to collect data from prospective trials such as PACS 01 (FEC versus FEC-docetaxel), PACS 04 (FEC versus epirubicin-docetaxel) and PACS 05 (FEC 6 courses versus 4 courses), to create the ALOPACS database.1- Roché H. Sequential Adjuvant Epirubicin-based Regimen and Docetaxel Chemotherapy for node-positive Breast Cancer Patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 dec 20; 24 (36) 5664-71.2- Sparano JA.Weekly Paclitaxel in the Adjuvant Treatment in Breast Cancer. N Engl J Med. 2008 Apr 17; 358(16): 1663-71. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3174.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 2_Supplement ( 2009-01-15), p. 6122-
    Abstract: Abstract #6122 Background : wPC and E are effective in the treatment of MBC. The main objective was to determine the efficacy of combined induction with wPC and E followed by consolidation with wPC. Secondary objective were to determine tolerance survivals and characterize antiangiogenic PC activity and predictive values of plasmatic neurotrophic and endothelial factors, in terms of neurotoxicity and efficacy. & #x2028; Methods : patients (pts) with RECIST measurable metastasis were recruited from april 2004 to may 2006 : ages (18-75 y) PS≤2, prior neoadjuvant adjuvant chemotherapy (NA-A CT) was permited if & gt;6 month. 3 cycles [wPC 80 mg/m² (D1, D8, D15, reinduction D28) and epirubicine 100 mg/m² D15], were followed by wPC (no week rest). VEGF, IL6, IL6SR, BDNF were measured in plasma at baseline and C2. Evaluation was performed after 3 induction cycles and every 3 month. A Simon optimal two-stage design was performed with 13 objective responses, allowing to accrue 25 more patients (28 responses expected). & #x2028; Results : 54 patients: median age 58.5 (30-75); 81% had surgery, 53.7% radiotherapy and 40.7% had NA-A CT, 46.3% hormonotherapy. Metastatic sites were nodes (36) lung (36) liver (28) bone (23). 100% PC and 90% E dose were administered at C2 and C3. 49 patients were evaluable for response; 3 patients withdrawn for taxol hypersensitivity, 1 early death (GIII asthenia and dyspnea), 1 investigator's decision. ITT analysis was performed: 33 responses (ORR: 61 %) Median OS was 30 months. During induction, 16 grade III, 27 grade IV and 3 febrile neutropenia were reported. There were 13 serious adverse events. & #x2028; Consolidation was mainly associated with neurotoxicity n=28 (20pts), GIII (n=1; 3.6%) GIV (n=1; 3.6%), astenia n=26 (18pts) ), GIII n=1; 3.8% GIV n=1; 3.8%and onycholysis n=15 (13pts) ), GIII n=2 ; 13.4% GIV n=1; 6.7%. & #x2028; High initial VEGF plasma levels were correlated with poor survival s (PFS, OS) with an univariate cox model (OR=1.954, 95%CI 0.944-4.043, p=0.071 ; HR 4.437, 95%CI 1.731-11.371, p=0.0019). Thresholds were determined. No correlation were observed between neurotoxicity and IL6, IL6SR and BDNF plasma levels. & #x2028; Conclusion : Despite the significant but manageable haematologic toxicity, PC + E showed a high efficacy. VEGF plasma levels are predictive of the outcome and should be tested as antiangiogenic drugs targeting factors.This work was supported in part by BMS. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6122.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 6
    Online Resource
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    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 24_Supplement ( 2011-12-15), p. PD08-10-PD08-10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 24_Supplement ( 2011-12-15), p. PD08-10-PD08-10
    Abstract: Background Information: Relevant animal models of human breast cancer are currently lacking, especially regarding the triple-negative breast cancer (TNBC) subtype, for which efficient therapies are needed. Recent studies indicate that spontaneous canine mammary carcinomas (CMCs) (which are common in France due to absence of early neutering) resemble human breast cancers, by pathology, tumor genetics, and biological behavior. However, the current molecular classification of human breast cancer has not been evaluated in canine samples yet. Objective: To establish the prognostic value of the human immunophenotypic classification in dogs To evaluate CMCs as a model of human breast cancer including TNBC. Methods: 350 CMCs treated by surgery alone were obtained from the Nantes Atlantic College of Veterinary Medicine, Food Science and Engineering (France) from 2005 to 2008. Recorded clinical data included breed, neutering, age at diagnosis, presence of metastases, cause and time to death. Histological records included the subtype of carcinoma, Elston & Ellis grade, presence of emboli and lymph node metastasis. By immunohistochemistry (IHC) using ER, PR, Her2 (Herceptest and Pathway® Her2), CK5/6, EGF-R and KI67, CMCs were classified into the subtypes of human breast cancer according to Nielsen et al. IHC analyses were independently reviewed by four pathologists. Results: The preliminary data in this abstract are based on 200 cases. The mean age at diagnosis was 10.8±2.1 years. 72,7% of dogs were intact female (27,3% of late neutering). 41% of dogs died due to cancer progression (metastasis rate of 30%). The most common histologic subtype was simple tubulopapillary CMC (53%), then solid CMC (32%). The most common grades were grade II (49%) and III (43%). 53% of the tumours showed lymphatic emboli. 4 immunophenotypes were defined: luminal A (11.9%), luminal B (5.1%), basal-like (59.3%) and non basal-like (23.7%) triple negative CMCs. 8.8% of the CMCs were scored Her2 2+ but none were considered Her2-overexpressing as defined by a 3+ score, despite appropriate staining with the two well established methods. Predictive factors for specific survival were: dog weight (p=0.01), histologic subtype (p=0.001), presence of emboli (p & lt;0.0001) or lymph node metastasis (p=0.02), Ki67 index (p=0.03). Triple-negative carcinomas showed a significantly shorter specific survival (median=224 days) when compared to luminal A CMCs (median=641 days) (MannWhitney, p=0.016). Conclusion: The molecular classification of human breast cancer identifies 4 subtypes of invasive CMCs with different prognoses. In dogs, a low rate of luminal tumors are observed, and no Her2-overexpressing tumors are found (defined by a score of 3+ by Her2 immunohistochemistry). 83% of CMCs were of the triple-negative subtype, associated with a shorter survival, as reported in human breast cancer. Infiltrative mammary cancer in dogs could be an interesting model for preclinical investigations. Final data based on 350 animals will be presented at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD08-10.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 7
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 9, No. 5 ( 2021-05-01), p. 568-582
    Abstract: Dysregulation of lipid metabolism affects the behavior of cancer cells, but how this happens is not completely understood. Neutral sphingomyelinase 2 (nSMase2), encoded by SMPD3, catalyzes the breakdown of sphingomyelin to produce the anti-oncometabolite ceramide. We found that this enzyme was often downregulated in human metastatic melanoma, likely contributing to immune escape. Overexpression of nSMase2 in mouse melanoma reduced tumor growth in syngeneic wild-type but not CD8-deficient mice. In wild-type mice, nSMase2-overexpressing tumors showed accumulation of both ceramide and CD8+ tumor-infiltrating lymphocytes, and this was associated with increased level of transcripts encoding IFNγ and CXCL9. Overexpressing the catalytically inactive nSMase2 failed to alter tumor growth, indicating that the deleterious effect nSMase2 has on melanoma growth depends on its enzymatic activity. In vitro, small extracellular vesicles from melanoma cells overexpressing wild-type nSMase2 augmented the expression of IL12, CXCL9, and CCL19 by bone marrow–derived dendritic cells, suggesting that melanoma nSMase2 triggers T helper 1 (Th1) polarization in the earliest stages of the immune response. Most importantly, overexpression of wild-type nSMase2 increased anti–PD-1 efficacy in murine models of melanoma and breast cancer, and this was associated with an enhanced Th1 response. Therefore, increasing SMPD3 expression in melanoma may serve as an original therapeutic strategy to potentiate Th1 polarization and CD8+ T-cell–dependent immune responses and overcome resistance to anti–PD-1.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 24_Supplement ( 2013-12-15), p. OT3-1-10-OT3-1-10
    Abstract: Background The question of the additional benefit of adjuvant chemotherapy (CT) compared to hormonal therapy alone (HT) for women & gt;70 with ER+ / HER2- breast cancer (BC) and aggressive characteristics is still unsolved. This trial compares the impact of both strategies on overall survival (OS). Trial design Following surgery, ∼2,000 patients will have a Genomic Grade (GG) centrally performed on FFPE specimens. Those with a high or equivocal GG will be randomized HT alone vs HT+CT. Patients with low GG will be followed as an observational cohort. The study, on-going in France since April 2012, has been recently activated in Belgium. Eligibility criteria Any ER+ HER2- BC after complete surgery, M0, any pT or pN. Normal organ functions. No specific BC treatment before surgery. Contralateral BC, invasive BC after ductal carcinoma in situ and isolated local invasive relapse when adjuvant systemic treatment is considered are all eligible. Multifocal or bilateral are eligible according to focus with worst GG. The G8 screening tool is used as stratification criteria for randomization. Specific aims OS (all deaths) is the primary endpoint. Secondary objectives include competing events, cost-effectiveness and Q-TWiST analysis, geriatric dimension, acceptability/willingness and health-related quality of life including specific ELD15. The Lee's 4-year mortality score is calculated. Translational research will focus on prognostic biomarkers and pharmacogenetic, investigating also the impact of treatments on putative ageing biomarkers as CRAMP, stathmin, EF-1α and chitinase and telomeres length. Statistical methods Sample size based on 4-year OS (87.5 vs 80%), bilateral test, α = 0.05, β = 0.20 and HR = 0.60. In total, 129 events are expected, requiring 340 patients/arm. Considering those lost to follow-up, ∼700 patients in total should be included (5 extra patients/year). Present accrual and target accrual As of May 2013, 43 centres have included 406 Patients aged 70-88. Only 14 GG evaluations were not performed for the following reasons: Patients consent withdrawal (n = 3), tumour block not available for the GG test (n = 5), CT not a treatment option anymore (patients or investigator's decision) (n = 2) or tumour status (ER+/HER2-) not confirmed by central review (n = 4). 8 GG evaluations are on-going. Of 384 cases with GG report, 160 (42%), 151 (39%) and 65 (17%) were respectively GG-1 (low risk), GG-3 (high risk) and GG-EQ (equivocal); 8 (2%) tests failed for technical reasons. The proportion of high GG in the study (53%) is similar to those observed in previous studies in general BC populations (40% to 60%). Of 216 GG-3/-EQ cases, 4 were not randomized because of distant metastases detected during extensive work-up (n = 3) and Patient refusal of CT treatment before randomization (n = 1). Five randomizations are on-going. GG determination was obtained in 384 leading to randomization in 207, totalizing so far 30% of the projected recruitment for the primary objective. This confirms the feasibility of such multicentre strategic program with an innovative prognostic signature in the elderly BC population. Contact information c-orsini@unicancer.fr. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-10.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 24_Supplement ( 2013-12-15), p. P2-05-08-P2-05-08
    Abstract: INTRODUCTION Among breast cancers, the triple negative subtype (negative for hormone receptors and not overexpressing HER2) has the worst prognosis and its response to Iniparib has been investigated in clinical trials. Further investigations are needed to optimize drug schedule and patient selection criteria. Iniparib antitumor mechanism is not completely understood, as well as iniparib diffusion kinetic into tumoral tissues. We address these questions in spontaneous canine invasive mammary carcinomas, which are a good model for this cancer subtype (Ibisch et al., World Veterinary Cancer Congress 2012), in a neoadjuvant setting. To our knowledge, this is the first study of iniparib administration in cancer-bearing dogs. MATERIAL AND METHODS Twenty female dogs with spontaneous MT with malignant criteria (tumor size, speed of growth, ulceration, relapse, or metastasis) were included. All tumors were described as rapidly growing. Dogs received a first infusion of iniparib at day 0 and a combination of carboplatin and iniparib at day 7. Biological materials (tumor biopsies and blood) were collected before and 5 minutes after iniparib infusion for pharmacokinetic and metabolism studies. Tumor response was evaluated by caliper measurements and histopathological analysis of mammary tumors and draining lymph nodes. A chain mastectomy was performed 3 or 4 weeks later. Histological records included the subtype of carcinoma (WHO 1999), Elston & Ellis grade, presence of emboli, lymph node metastasis and IHC stainings using ER, PR, Her2 (scored according to Wolff et al.2007), CK5/6, EGF-R and Ki67. Intensity of necrosis and apoptosis was evaluated using PAS coloration and immunohistochemistry for caspase 3, at DO on tumor biopsies and at surgery. Toxicity of the protocol was evaluated and its efficiency on invasive carcinomas was compared to surgery alone (control group of 27 female dogs with invasive mammary carcinomas treated by chain mastectomy alone). RESULTS Treated and control groups shared similar features concerning animal breeds, age, neutering status and tumor location. 75% of the treated MT were malignant. Necrosis and apoptosis were significantly increased in respectively 63 and 56% of iniparib treated tumors. Clinical evidence of toxicity was minimal (15% of dogs with nausea, 60% with transient polyuria-polydipsia). Tumor stabilization was observed before surgery in all dogs but one. Median survival has not been reached. CONCLUSION Iniparib at 35mg/kg combined with carboplatin at 300 mg/m2 seemed well tolerated in this study and deserves further investigations. The degree of necrosis and apoptosis in the treated tumors can be evaluated with these techniques. Iniparib pharmacokinetic and metabolism studies in cancer-bearing dogs are ongoing. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-08.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 10
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    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 24_Supplement ( 2013-12-15), p. P2-05-05-P2-05-05
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 24_Supplement ( 2013-12-15), p. P2-05-05-P2-05-05
    Abstract: Background: Dogs spontaneously develop invasive mammary carcinoma with a high prevalence of the triple-negative subtype, making this model relevant for the investigation of new therapeutic pathways. Insulin-like growth factor-1 receptor (IGF-1R) is extensively involved in malignant transformation, proliferation and metastasis in human breast cancer and multiple clinical trials have used IGF-1R inhibitors with encouraging results. Aims: To quantify IGF-1R expression in canine triple-negative invasive mammary carcinoma (TN-CMC) and assess its prognostic value (overall, specific and disease-free survival). To validate the dog as a spontaneous animal model for preclinical trials targeting IGF-1R in triple-negative breast cancer. Material and methods: 104 triple-negative canine invasive mammary carcinomas (Estrogen receptor negative, Progesterone receptor negative, not HER2 overexpressing) were included. Bitches were followed for at least 2 years after mastectomy. TN-CMC were classified as basal-like (Cytokeratin-CK 5/6 positive and/or Epidermal Growth Factor Receptor-EGFR positive) and non-basal-like (CK 5/6 and EGFR negative). IGF-1R expression (clone G11) was quantified using the same scoring system as for HER2 in breast cancer. Results: 68.3% (n = 71/104) of the TN-CMC were classified as basal-like and 31.7% (n = 33/104) as non-basal-like. 45.2% (n = 47/104) of TN-CMC overexpressed IGF-1R (score 3+), of which 70.2% (n = 33/47) were basal-like and 61.7% (n = 29/47) were grade III. Univariate and multivariate analyses revealed that IGF-1R overexpression (score 3+) was associated with significantly shorter overall, specific and disease-free survivals (median: 163, 332 and 278 days respectively) than weak (score 1+) IGF-1R expression (median: 842 days, not achieved and 1011 days respectively). Conclusion and perspectives: IGF-1R overexpression is common and related to a poor outcome in canine triple-negative invasive mammary carcinoma. Preclinical studies using the dog as a spontaneous animal model for triple-negative breast cancer could be considered to investigate new therapies targeting IGF-1R. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-05.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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