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  • American Association for Cancer Research (AACR)  (13)
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  • American Association for Cancer Research (AACR)  (13)
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  • 1
    Online Resource
    Online Resource
    Abstract S1-7: Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer – First efficacy results from the LEA study.
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 24_Supplement ( 2012-12-15), p. S1-7-S1-7
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 24_Supplement ( 2012-12-15), p. S1-7-S1-7
    Abstract: Background: Preclinical data (de la Haba J, AACR 2011) and retrospective clinical data (Mander P, Cancer 2003; Linderhol B, JCO 2000) suggest that high vascular endothelial growth factor (VEGF) levels in breast tumors are associated with a decreased response to endocrine therapy. We designed the randomized phase III LEA study of first-line bevacizumab in combination with hormone therapy in endocrine responsive advanced breast cancer patients to address the hypothesis that anti-VEGF treatment can prevent resistance to hormone therapy in these patients. Methods: A multicenter, bi-national, randomized, open label, phase III study investigated the addition of Bevacizumab (B) 15mg/kg every 3 weeks to an endocrine therapy (ET) with letrozole (2.5 mg/day) or fulvestrant (250mg/4 weeks) as first-line therapy in advanced breast cancer. Postmenopausal patients with HER2-negative and hormone-receptor-positive breast cancer were eligible and randomized in a 1:1 ratio after being stratified for prior adjuvant therapy with an aromatase inhibitor (AI); number of involved sites (one/multiple); measurable lesions (yes/no) and participating country (Spain/Germany). The primary objective was to compare progression-free survival (PFS) between treatment arms. Secondary objectives were overall survival, time to treatment failure, overall response rate, response duration, clinical benefit rate, and safety. In total, 344 patients (172 in each treatment arm) were needed to detect a hazard ratio of 0.69 (corresponding to a median PFS of 9 months in the ET arm and 13 months in the ET+B arm) with α=0.05 and β=0.2. With an expected drop-out rate of 10%, 378 patients were to be included. The efficacy analysis is pre-planned after 270 events. Results: From 11/2007 to 8/2011, 380 patients were randomized in Spain and Germany to ET (n = 189) or ET+B (n = 191), 342 patients received letrozole and 38 fulvestrant. Baseline characteristics were well balanced. Median age was 65 years (38–86) and 72% of patients had ECOG PS 0. Twelve patients (4%) entered the trial with locally advanced disease, 65% had measurable lesions, 63% had bone and 45% visceral metastasis. 76% of patients had both hormone receptor positive. 44% had adjuvant chemotherapy and 51% adjuvant endocrine therapy from which 36% of patients received adjuvant AI. Full safety data will be presented at ESMO this year. The main side effects (any grade, per patient, ET+B vs ET) were anemia 76% vs 44%, p & lt; 0.001; fatigue 50% vs 31%, p = 0.001; hemorrhage 19% vs 2%, p & lt; 0.001; hypertension 55% vs 12%, p & lt; 0.001; proteinuria 21%vs 3%, p & lt; 0.001; and thrombosis grade 3–4, 2.3% vs 0%, p = 0.057. Until June 2012, 226 PFS events have been observed. The current event rate holds out the expectation to have the 270 necessary events by August-2012. Conclusions: LEA is the first phase III study to explore the use of an anti-angiogenic drug in combination with endocrine therapy. The efficacy results will be presented at the meeting. First and second authors have contributed equally to this study Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-7.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS12-S1-7
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 2
    Online Resource
    Online Resource
    Abstract P3-07-03: PIK3CA mutations predict resistance to trastuzumab/pertuzumab and nab -paclitaxel in primary HER2-positive breast cancer – Massive parallel sequencing analysis of 293 pretherapeutic core biopsies of the GeparSepto study
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 4_Supplement ( 2016-02-15), p. P3-07-03-P3-07-03
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 4_Supplement ( 2016-02-15), p. P3-07-03-P3-07-03
    Abstract: Background: Phosphatidylinositol 3-kinase mutations (PIK3CA) are common in breast cancer (BC). Mutations are predominantly found in hot-spots located in the helical and kinase domains (exons 9 and 20). We recently demonstrated that PIK3CA mutations predict lower pathological complete response (pCR) to double blockade with trastuzumab/lapatinib in HER2+ve primary BC. Methods: We evaluated PIK3CA mutations in 293/403 HER2+ve tumors of participants of the neoadjuvant GeparSepto (G7) study (Untch et al. SABCS 2014). The G7 study investigated the effect of exchanging paclitaxel for nab-paclitaxel prior to EC. All patients received trastuzumab and pertuzumab. The G7 study showed a significantly higher pCR rate in patients receiving nab-paclitaxel. HER2, hormone receptors (HR), Ki67 and tumor infiltrating lymphocytes (TILs) were centrally assessed prior to randomization. PIK3CA mutations in exons 9 and 20 were evaluated in formalin-fixed, paraffin embedded core biopsies taken before therapy using deep targeted massive parallel sequencing with a minimum coverage of 500 and a mean coverage of 6520 and 6346 per amplicon, (exon9 and exon 20). Only non-synonymous mutations in the coding region that were called at variant allele frequency ≥10% were taken into consideration. Only cases with a tumor cell content of ≥20% were included. Results: In the G7 study, 396 patients with HER2+ve BC have been randomized from 06/2012 to 01/2014 and started treatment. From these 293 could be sequenced. Median age in the analyzed cohort was 49 years (range 22-75); most tumors were cT1-2 (89.9%); cN0 (54.4%); ductal invasive (88.7%), grade 3 (53.9%), HR+ve (69.6%), Ki67 & gt;20% (69.3%), LPBC-negative (83.2%). Overall, 22.2% of the tumors were found to have a PIK3CA mutation, 20.1% in HR+ve and 27.0% in HR-ve. Overall, the pCR rate was significantly lower in the PIK3CA mutant tumors compared to the wild type (wt) group (47.7% vs. 66.7%; p=0.009). This effect was seen both in the HR+ve (43.9% vs. 61.3%; p=0.052) and the HR-ve population (54.2% vs. 80.0%; p=0.029). There was also a significant difference in pCR according to PIK3CA mutation status dependant on the taxane. In the nab-paclitaxel group, pCR rates were significantly lower in patients with PIK3CA mutations compared to those without PIK3CA mutations (38.7% vs. 72.0%; p=0.001), whereas in the paclitaxel group, there was no significant difference between patients with and without a PIK3CA mutation (55.9% vs. 60.9%; p=0.690). The respective interaction could be demonstrated in univariate (p=0.039) as well as multivariate regression analysis (p=0.010) after adjusting for known baseline factors. Conclusion: Patients with PIK3CA mutant HER2+ve BC have a significantly lower pCR rate compared to patients with wt tumors. In contrast to the results with double anti-HER2 blockade consisting of trastuzumab/lapatinib, the effect was evident irrespective of the HR status. In addition, PIK3CA mutation status was significantly associated with higher pCR following nab-paclitaxel. The project has partly been funded within the EU-FP7 project RESPONSIFY No 278659 and the German Cancer Consortium (DKTK). Citation Format: Loibl S, Budczies J, Weichert W, Furlanetto J, Stenzinger A, Pfarr N, von Minckwitz G, Jackisch C, Schneeweiss A, Fasching P, Schmatloch S, Aktas B, Nekljudova V, Weber K, Untch M, Denkert C. PIK3CA mutations predict resistance to trastuzumab/pertuzumab and nab-paclitaxel in primary HER2-positive breast cancer – Massive parallel sequencing analysis of 293 pretherapeutic core biopsies of the GeparSepto study. [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 P3-07-03.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS15-P3-07-03
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 3
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    Abstract P1-14-11: nab-paclitaxel at a dose of 125 mg/m2 weekly is more efficacious but less toxic than at 150 mg/m2. Results from the neoadjuvant randomized GeparSepto study (GBG 69)
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 4_Supplement ( 2016-02-15), p. P1-14-11-P1-14-11
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 4_Supplement ( 2016-02-15), p. P1-14-11-P1-14-11
    Abstract: Background: We previously reported that nab-paclitaxel (nP) increases the pathological complete response (pCR, ypT0 ypN0) rate when it replaces solvent-based paclitaxel (P) as part of a sequential taxane followed by epirubicin/cyclophosphamide (EC) neoadjuvant chemotherapy for patients with early breast cancer (Untch et al. SABCS 2014). Here, we report efficacy and safety of patients being treated either with 150 mg/m2 nab-paclitaxel (nP150) before an amendment or with 125 mg/m2 nab-paclitaxel (nP125) thereafter in comparison to solvent-formulated paclitaxel at 80 mg/m2 (P80). Methods: In the GeparSepto study (NCT01583426), 1207 patients were randomized to either nP150 or P80 q1w for 12 weeks followed by 4 cycles of conventionally dosed EC (E: 90mg/m2; C: 600 mg/m2) q3w. The primary objective of the study was to compare the pCR rate (pCR, ypT0 ypN0). Patients with untreated, histologically confirmed uni- or bilateral, cT2- cT4d carcinoma, and no clinically relevant cardiovascular and other co-morbidities were included. Patients with HER2+ tumors received trastuzumab (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly to all chemotherapy cycles. After a safety analysis showed a higher rate of dose reductions and treatment discontinuations with nP150 compared to P80, weekly dose of nP was reduced to 125 mg/m2. Results: nP was given for the majority of cycles at a dose of 150 mg/m2 to 179 patients and at a dose of 125 mg/m2 to 426 patients. Treatment characteristics were fairly balanced between these two sequential cohorts as well as compared to 601 patients receiving P80 except for HER2 status (HER2-positive: nP150 22%, nP125 37% and P80 33%) and Ki67 ( & lt;20%: nP150 60%, nP125 73% and P80 69%). Taxane treatment was discontinued in 16% (nP150), 11% (nP125) and 6% (P80) of patients, respectively. Median dose per cycle (based on relative total dose intensity (RTDI)) was 129 mg/m2 with nP150, 119 mg/m2 with nP125 and 78 mg/m2 with P80, respectively. Peripheral sensory neuropathy (PNP) grade 3/4 (NCI-CTCAE v4.0) was observed in 15% with nP150, 8% with nP125 and 3% with P80, respectively. pCR was 32% with nP150, 41% with nP125 and 29% with P80 in all patients and 46% with nP150, 49% with nP125 and 26% with P80 in 277 patients with triple-negative breast cancer, respectively. Conclusions: Risk-benefit ratio of nP125 was improved over nP150 with better drug adherence and RTDI, lower frequency of PNP but a higher pCR rate. It should therefore be considered as the preferred schedule when nP is used as neoadjuvant treatment for primary breast cancer. The trial was financially supported by Celgene and Roche. Citation Format: von Minckwitz G, Untch M, Jakisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Weibringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer J-U, Clemens M, Costa SD, Gerber B, Nekljudova V, Loibl S. nab-paclitaxel at a dose of 125 mg/m2 weekly is more efficacious but less toxic than at 150 mg/m2. Results from the neoadjuvant randomized GeparSepto study (GBG 69). [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 P1-14-11.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS15-P1-14-11
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 4
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    Gene Expression–Based Prediction of Neoadjuvant Chemotherapy Response in Early Breast Cancer: Results of the Prospective Multicenter EXPRESSION Trial
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 8 ( 2021-04-15), p. 2148-2158
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 8 ( 2021-04-15), p. 2148-2158
    Abstract: Expression-based classifiers to predict pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) are not routinely used in the clinic. We aimed to build and validate a classifier for pCR after NACT. Patients and Methods: We performed a prospective multicenter study (EXPRESSION) including 114 patients treated with anthracycline/taxane-based NACT. Pretreatment core needle biopsies from 91 patients were used for gene expression analysis and classifier construction, followed by validation in five external cohorts (n = 619). Results: A 20-gene classifier established in the EXPRESSION cohort using a Youden index–based cut-off point predicted pCR in the validation cohorts with an accuracy, AUC, negative predictive value (NPV), positive predictive value, sensitivity, and specificity of 0.811, 0.768, 0.829, 0.587, 0.216, and 0.962, respectively. Alternatively, aiming for a high NPV by defining the cut-off point for classification based on the complete responder with the lowest predicted probability of pCR in the EXPRESSION cohort led to an NPV of 0.960 upon external validation. With this extreme-low cut-off point, a recommendation to not treat with anthracycline/taxane-based NACT would be possible for 121 of 619 unselected patients (19.5%) and 112 of 322 patients with luminal breast cancer (34.8%). The analysis of the molecular subtypes showed that the identification of patients who do not achieve a pCR by the 20-gene classifier was particularly relevant in luminal breast cancer. Conclusions: The novel 20-gene classifier reliably identifies patients who do not achieve a pCR in about one third of luminal breast cancers in both the EXPRESSION and combined validation cohorts.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-2662
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 5
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    Online Resource
    ROBO1 Promotes Homing, Dissemination, and Survival of Multiple Myeloma within the Bone Marrow Microenvironment
    American Association for Cancer Research (AACR) ; 2021
    In:  Blood Cancer Discovery Vol. 2, No. 4 ( 2021-07-01), p. 338-353
    Details
    In: Blood Cancer Discovery, American Association for Cancer Research (AACR), Vol. 2, No. 4 ( 2021-07-01), p. 338-353
    Abstract: The bone marrow (BM) microenvironment actively promotes multiple myeloma pathogenesis, and therapies targeting both cancer cells and the niche are highly effective. We were interested in identifying novel signaling pathways supporting multiple myeloma–BM cross-talk. Mutations in the transmembrane receptor Roundabout 1 (ROBO1) were recently identified in patients with multiple myeloma; however, their functional consequences are uncertain. Through protein structure–function studies, we discovered that ROBO1 is necessary for multiple myeloma adhesion to BM stromal and endothelial cells and that ROBO1 knockout (KO) compromises BM homing and engraftment in a disseminated mouse model. ROBO1 KO significantly decreases multiple myeloma proliferation in vitro and intra- and extramedullary tumor growth in vivo. Mechanistically, the ROBO1 C-terminus is cleaved in a ligand-independent fashion and is sufficient to promote multiple myeloma proliferation. Vice versa, mutants lacking the cytoplasmic domain, including the human-derived G674* truncation, act dominantly negative. Interactomic and RNA-sequencing studies suggest that ROBO1 may be involved in RNA processing, supporting further studies. Significance: ROBO1 is highly expressed in t(4;14) multiple myeloma and supports homing and dissemination to the BM niche. ROBO1 knockout causes reduced tumor growth in intramedullary and extramedullary myeloma animal models, while the ROBO1 C-terminus is cleaved in multiple fragments and it is necessary and sufficient to sustain myeloma proliferation.
    Type of Medium: Online Resource
    ISSN: 2643-3230 , 2643-3249
    URL: Article
    DOI: 10.1158/2643-3230.BCD-20-0164
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 6
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    OT3-01-15: Phase III Trial Evaluating the Addition of Bevacizumab to Endocrine Therapy as First-Line Treatment for Advanced Breast Cancer: The LEA Study.
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 24_Supplement ( 2011-12-15), p. OT3-01-15-OT3-01-15
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 24_Supplement ( 2011-12-15), p. OT3-01-15-OT3-01-15
    Abstract: Background Retrospective clinical data suggest that high vascular endothelial growth factor (VEGF) levels in breast tumors are associated with a decreased response to endocrine therapy. We designed the randomized phase III LEA study of first-line bevacizumab in combination with endocrine therapy, to address the hypothesis that anti-VEGF treatment can prevent resistance to endocrine therapy in patients with advanced breast cancer sensitive to such treatment. Methods: Postmenopausal patients with evaluable locally recurrent or metastatic breast cancer, HER2−negative- and estrogen receptor (ER)-and/or progesterone receptor (PgR)-positive disease, and eligible to receive hormonal treatment are candidates for this study. Patients are randomized to receive letrozole 2.5mg daily or fulvestrant, 250mg every 4 weeks (Arm A) or the same hormonal therapy plus bevacizumab 15mg/kg every 3 weeks (Arm B). The primary objective is to compare progression-free survival (PFS) between the treatment arms. Secondary endpoints are overall survival, time to treatment failure, overall response rate, response duration, clinical benefit rate and safety. In total, 344 patients (172 in each treatment arm) will be needed to detect a hazard ratio of 0.69 (corresponding to a median PFS of 9 months in Arm A and 13 months in Arm B) with a power of 80% and a two-tailed log-rank test at 0.05. With an expected drop-out rate of 10%, 378 patients will be included. Efficacy analysis will be triggered after 270 events. Results: Recruitment began in November 2007. To date, 348 patients have been included in the study in Spain (n=244) and Germany (n=104). We anticipate completing recruitment by September 2011. Baseline characteristics of the first 334 randomized patients are shown in the table. Conclusions: LEA is the first study to explore the use of an anti-angiogenic drug in combination with endocrine therapy in the context of a phase III study. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-15.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS11-OT3-01-15
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 7
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    Abstract OT1-02-02: The DETECT study program – Personalized treatment in metastatic breast cancer based on circulating tumor cells
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 4_Supplement ( 2016-02-15), p. OT1-02-02-OT1-02-02
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 4_Supplement ( 2016-02-15), p. OT1-02-02-OT1-02-02
    Abstract: Circulating tumor cells (CTCs) are found in patients with primary and metastatic breast cancer (MBC), respectively, and discordance in HER2 and hormone-receptor status between primary tumor, metastases and CTCs is well described. Treatment decisions are still based on the expression profile of solid tumor samples whereas CTCs are thought to cause tumor progression by blood-derived metastases. Nevertheless, targeted therapy based on expression profile of CTCs is not established in clinical routine. Individualized treatment decisions based on presence and phenotype of CTCs will be analyzed within the DETECT study program. Metastatic breast cancer patients with HER2-negative MBC are screened in DETECT III and IV for presence of CTCs by using the CellSearch System (Janssen Diagnostics) which is FDA approved for enumeration of CTCs. Patients are enrolled into the different cohorts according to HER2-phenotype of CTCs. Since February 2012, women with HER2-negative MBC and HER2-positive CTCs are treated in the multicenter randomized Phase III study DETECT III with standard therapy with or without additional HER2-targeted therapy with Lapatinib. For standard therapy, physicians can choose between exemestane, letrozole and anastrozole for endocrine therapy, or docetaxel, paclitaxel, capecitabine, vinorelbine and non-pegylated liposomal doxorubicin for chemotherapy. Efficacy of CTC-based anti-HER2 treatment is evaluated by analyzing CTC-clearance rate after treatment. Patients with only HER2-negative CTCs are recruited for the multicenter open-label phase II study DETECT IV. Since December 2013, women with hormone-receptor positive MBC receive endocrine therapy (tamoxifen, exemestane, letrozole or anastrozole) plus everolimus in DETECT IVa. In February 2015, DETECT IV was extended by the eribulin-cohort which offers a cytotoxic treatment with eribulin for women with triple-negative or hormone-receptor positive, chemotherapy demanding MBC (DETECT IVb). Progression free survival is used for assessment of clinical efficacy with overall survival and disease control rate as secondary objectives. DETECT V, a multicenter open-label phase III study starting in summer 2015, randomizes patients with hormone-receptor positive, HER2-positive MBC to a dual HER2 targeted therapy (Trastuzumab and Pertuzumab) combined with either endocrine therapy or cytotoxic treatment. Quality of life determined by occurrence of adverse events is compared between both treatment arms. For prediction of endocrine treatment response, an "Endocrine Responsiveness Score" is calculated based on expression of estrogen-receptor and HER2 on detected CTCs. More than 1200 patients are already screened in the DETECT study concept. Thus, it is the worldwide largest study concept with therapy decisions resulting from CTC-testing and CTC-phenotypization. The accompanying translational research programs evaluates further markers for molecular characterization of CTCs and prediction of therapy response. Conclusion and Contact The value of CTC phenotypes for making decisions on therapy interventions and predicting treatment responses in patients with MBC is tested in the DETECT study concept. The findings will help to move a step forward towards a more personalized anti-cancer therapy. Citation Format: Schramm A, Friedl TWP, Huober J, Jäger B, Rack B, Trapp E, Fasching PA, Taran F-A, Hartkopf A, Schneeweiss A, Müller V, Aktas B, Pantel K, Meier-Stiegen F, Wimberger P, Kümmel S, Gebauer G, Müller L, Janni W, Fehm T. The DETECT study program – Personalized treatment in metastatic breast cancer based on circulating tumor cells. [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 OT1-02-02.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS15-OT1-02-02
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 8
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    Abstract LB217: ROBO1 promotes homing, dissemination, and survival of multiple myeloma within the bone marrow microenvironment
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB217-LB217
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB217-LB217
    Abstract: Introduction: The bone marrow (BM) niche promotes multiple myeloma (MM) growth, survival and drug resistance. Therapies targeting both cancer cells and the microenvironment are highly effective. We were interested in identifying novel signaling pathways supporting MM pathogenesis through MM-BM crosstalk. The transmembrane receptor Roundabout 1 (ROBO1) plays a role in growth and dissemination of solid tumors, however its function in MM is unknown. Material and Methods: We analyzed ROBO1 expression in cell lines and primary samples via western blot, immunohistochemistry (IHC) and gene expression profiling. We used short hairpin RNA and CRISPR-Cas9 for ROBO1 knock down (KD) and knock out (KO), respectively. For protein structure-function and rescue studies, we stably expressed full-length (FL) or mutant ROBO1 devoid of extracellular (Cyt) or intracellular domain (DeltaCyt), including patient-derived G674* truncation, with a C-terminus FLAG tag. We used a 3D hydrogel encapsulation system to study proliferation; FLAG immunoprecipitation (IP) followed by mass spectrometry to identify ROBO1 interacting partners; and immunofluorescence to detect ROBO1 localization. To study tumor growth in vivo, we performed PET-CT of mice inoculated subcutaneously or intramedullary with WT or ROBO1 KO MM cells and retrieved tumors for RNA sequencing. To study dissemination and homing, KO and FL addback MM cells were injected intravenously in SCID mice. Mice were monitored for development of tumors or hindlimb paralysis and femora/tumors harvested once mice reached endpoint. Results: ROBO1 is highly expressed in MM cell lines and primary cells but low/absent in normal plasma cells and other hematologic cancer cell lines. ROBO1 KD is specifically cytotoxic for MM cells and ROBO1 KO decreases proliferation, a phenotype fully rescued by FL ROBO1. Compared to WT, ROBO1 KO significantly decreases intramedullary (mean tumor volume (MTV): 1323 vs 457 mm3, p value= 0.02) and extramedullary (MTV: 2684 vs 823 mm3, p value= 0.001) tumor growth in vivo. We further discovered that ROBO1 KO decreases adhesion of MM to BM endothelial and BMSC, which is fully rescued by FL ROBO1. In a disseminated mouse model, ROBO1 KO cells generate bone plasmacytoma with reduced BM invasion, as compared to the extensive BM infiltration observed with ROBO1 FL cells. Consistently, in primary samples from patients, we detected ROBO1 expression only in 1 out of 10 solitary plasmacytoma (dim staining) as compared to 14 out of 14 MM bone marrow biopsy samples tested (11 strong, 3 dim, p value= 0.0001). Mechanistically, we show for the first time that ROBO1 C-terminus is cleaved in a ligand-independent fashion; translocates to the nucleus; and is necessary and sufficient to rescue ROBO1 KO proliferative defect. Viceversa, mutants lacking the cytoplasmic domain, including the G674* truncation, act dominantly negative. Interactomic and RNA sequencing studies point to a previously unknown function of ROBO1 in RNA processing, setting the bases for future studies. Conclusions: We show for the first time that ROBO1 is necessary for MM growth and homing to the BM. Cleaved ROBO1 cytosolic domain translocates to the nucleus and is necessary and sufficient to rescue ROBO1 KO proliferative defect, possibly by participating in RNA processing. These data suggest that ROBO1 C-terminus may be a novel molecular target in MM. Citation Format: Giada Bianchi, Peter G. Czarnecki, Matthew Ho, Aldo M. Roccaro, Antonio Sacco, Yawara Kawano, Annamaria Gulla, Anil Aktas Samur, Tianzeng Cheng, Kenneth Wen, Yu-Tzu Tai, Maria Moscvin, Xinchen Wu, Gulden Camci-Unal, Matteo Claudio Da VIa, Niccolo Bolli, Ruben D. Carrasco, Irene M. Ghobrial, Kenneth C. Anderson. ROBO1 promotes homing, dissemination, and survival of multiple myeloma within the bone marrow microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB217.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-LB217
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 9
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    Abstract P4-21-06: Dual HER2-blockade with pertuzumab and trastuzumab in HER2-positive early breast cancer: A subanalysis of data from the randomized phase III GeparSepto trial
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 4_Supplement ( 2017-02-15), p. P4-21-06-P4-21-06
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 4_Supplement ( 2017-02-15), p. P4-21-06-P4-21-06
    Abstract: Background Our recent randomized, multicenter phase III GeparSepto study (Untch M et al. Lancet Oncol 2016) found that substituting nab-paclitaxel for standard solvent-based paclitaxel significantly improved the pathologic complete response (pCR) rate in patients receiving a sequential regimen of taxane, epirubicin and cyclophosphamide as neoadjuvant treatment for high-risk primary breast cancer. Patients with HER2-positive tumors (32.8%; n=396) also received a combination of pertuzumab and trastuzumab: the present analysis focuses on efficacy and safety data from these HER2+ patients treated with the dual-blockade. Methods Patients with histologically confirmed early breast cancer (n = 1206) received either weekly paclitaxel 80mg/m2 or weekly nab-paclitaxel 150/125mg/m2, according to randomization), followed by four cycles of epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 q3w, with concurrent trastuzumab 6 mg/kg (loading (LD) dose 8 mg/kg) and pertuzumab 420 mg (LD 840 mg) q3w for those with HER2-positive tumors. The primary endpoint was pathologic complete response (pCR), defined as ypT0 ypN0. Results The GeparSEPTO trial included 396/1206 (32.8%) HER2+ primary breast cancer patients. 27.0% in the HER2-positive and 34.1% in the HER2-negative group had HR-negative disease. Baseline characteristics were otherwise comparable between HER2+ and HER2- patients. Higher rates of pCR were seen in HER2+, compared to HER2- tumors (57.8% vs 22.0%). The highest overall pCR rate was observed in the HER2+/HR- cohort with 71.0%; 66.7% with Pac and 74.6% with nab-Pac. In HER2+/HR+ pCR rate was 52.9% ; 49.4% with Pac and 56.4% with nab-Pac. Using the definition ypT0/is ypN0 for pCR; pCR rates were generally higher especially in the HER2+ cohort (66.2% (ypT0/is ypN0) vs 57.8% (ypT0 ypN0)) compared to 25.2% (ypT0/is ypN0) vs 22% (ypT0 ypN0)) in patients with HER2-negative tumors. The HER2+ patients experienced a significantly higher incidence of grade 3-4 adverse events 85.4% vs 78.0% in the HER2-cohort, p=0.003); grade 3-4 hematologic AEs 74.0% (HER2+) vs 69.5% (HER2-); p=0.120 with grade 3-4 anaemia 2.5% vs 0.9%; p=0.034); any grade thrombopenia 28.5% vs 21.8%; p=0.012) and febrile neutropenia 6.3 vs 3.3%; p=0.023. Any grade 3-4 non-haematological toxicities occurred in 38.4% vs 30.1%; p=0.005), with grade 3-4 diarrhea occurring in 7.6% vs 0.9%; p & lt;0.001 of the patients. This had no impact on compliance. LVEF decreases from baseline were uncommon (7.6%) with 2.0% (HER2+) versus 0.4% (HER2-) of patients showing decreases to & lt;50% along with a ≥10% decrease from baseline. Conclusion This is the largest cohort of patients with HER2-positive early breast cancer receiving a dual HER2-targeted neoadjuvant therapy of pertuzumab and trastuzumab, together with nab-paclitaxel or paclitaxel followed by epirubicin and cyclophosphamide. HER2+ patients experienced more noteworthy toxicity. The pCR rate were higher in the HER2+ cohort receiving the dual blockade and was highest in patients with in HER+/HR- particularly if nab-paclitaxel was substituted for paclitaxel. The trial is financially supported by Celgene and Roche. Citation Format: Loibl S, Jackisch J, Schneeweiss A, Schmatloch S, Aktas B, Denkert C, Schem C, Wiebringhaus H, Kuemmel S, Luebbe K, Warm M, Just M, Hanusch C, Hackmann J, Blohmer J-U, Clemens M, Engels K, Nekljudova V, von Minckwitz G, Untch M. Dual HER2-blockade with pertuzumab and trastuzumab in HER2-positive early breast cancer: A subanalysis of data from the randomized phase III GeparSepto trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-06.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS16-P4-21-06
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 10
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    Abstract P5-16-03: Peripheral sensory neuropathy occurrence and resolution: Results from the neoadjuvant randomized GeparSepto study (GBG 69)
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 4_Supplement ( 2017-02-15), p. P5-16-03-P5-16-03
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 4_Supplement ( 2017-02-15), p. P5-16-03-P5-16-03
    Abstract: Background: The GeparSepto (NCT01583426) study showed that nab-paclitaxel (nP) increases the pathological complete response (ypT0 ypN0) rate when it replaces paclitaxel (P) as part of a sequential taxane followed by epirubicin/cyclophosphamide (EC) neoadjuvant chemotherapy for pts with early breast cancer (BC) (Untch Lancet Oncol 2016). After a safety analysis showed a higher rate of dose reductions, treatment discontinuations as well as peripheral sensory neuropathy (PSN) with nP 150 mg/m2 w (nP150) compared to P 80mg/m2 w, dose of nP was reduced to 125 mg/m2 w (nP125). The risk-benefit ratio of nP125 was improved over nP150 (von Minckwitz SABCS 2015). We reported follow-up (FU) data on PSN occurrence and resolution. Methods: Pts with untreated BC received P 80mg/m2 w or nP 150/125mg/m2 w followed by four cycles of E 90 mg/m2 plus C 600 mg/m2 q3w, with trastuzumab 6 mg/kg (loading (LD) dose 8 mg/kg) and pertuzumab 420 mg (LD 840 mg) q3w if HER2+. After the end of the study the protocol was amended in order to collect long-term data on PSN outcome as well as on treatment modalities. PSN will be reported according treatment and dose received on day 1. Results: Overall 601 pts received P80; 220 pts nP150 and 385 pts nP125 on day 1. PSN grade 2-4 was observed in 18.8% (n=113/601) of pts treated with P80 and in 41.8% (n=92/220) vs 39.2% (n=151/385) with nP150 and nP125 respectively (p=0.547). Grade 3-4 PSN was reported for 2.7% (n=16/601) of pts in the P80 group and 14.5% (n=32/220) vs 8.1% (n=31/385) in the nP150 vs nP125 group respectively (p=0.018). In 31.8% (36/113), 35.9% (33/92) and 27.2% (41/151), PSN was not resolved at the end of the treatment (EOT); PSN grade 3-4 was not resolved in 37.5% (6/16), 56.3% (18/32) and 58.1% (18/31). After a median FU of 110 weeks after EOT, data on PSN status for pts with unresolved PSN grade 2-4 were available from 30, 22 and 32 pts; 26 pts did not provide update information (n=7 died, n=5 data not yet available, n=14 status unknown). For 63.3% (n=19), 40.9% (n=9) and 56.2% (n=18) of pts, PSN grade 2-4 was resolved to grade 1. Time to resolve (TTR) of PSN grade 2-4 was significantly different between nP150 and nP125 (p & lt;0.001); no significant difference was seen between P and nP (p=0.405) [Tab.1]. After a median FU of 103 weeks after EOT, data on PSN status of pts with unresolved PSN grade 3-4 were available for 6, 14 and 14 pts. For 66.6% (n=4), 42.8% (n=6) and 50.0% (n=7) of pts PSN grade 3-4 was resolved to grade 1. TTR of PSN grade 3-4 was not significantly different neither for nP150 vs nP125 (p=0.103) nor for P vs nP (p=0.120) ) [Tab.1] . Conclusions: nP125 is associated with a lower occurrence of PSN compared to nP150 but higher PSN than P80. If PSN occurred nP125 is associated with a more rapid resolution compared to nP150. Nearly 10.7% had no resolution of PSN so far. Further FU and markers for selecting pts at risk are needed. The trial is supported by Celgene. Table 1. Median time to resolution (mTTR) of PSN to grade 1comparison groupsmTTR n (weeks); [95% CI]P vs nPPnP150nP125grade 2-47 [6-9] 8 [6-10]grade 3-49 [4-15] 17 [5-123]nP150 vs nP125 grade 2-4 13 [9-15] 6 [4-9]grade 3-4 56 [11-170] 17 [10-nr]abbreviations: nP, nab-paclitaxel; P, paclitaxel; nr, not reached Citation Format: Furlanetto J, von Minckwitz G, Jackisch C, Schneeweiss A, Aktas B, Denkert C, Wiebringhaus H, Kuemmel S, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer J-U, Clemens M, Costa SD, Gerber B, Nekljudova V, Untch M, Loibl S. Peripheral sensory neuropathy occurrence and resolution: Results from the neoadjuvant randomized GeparSepto study (GBG 69) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-03.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS16-P5-16-03
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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