GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • American Association for Cancer Research (AACR)  (15)
  • 1
    Online Resource
    Online Resource
    Biological characterization of MLN944: A potent DNA binding agent
    American Association for Cancer Research (AACR) ; 2004
    In:  Molecular Cancer Therapeutics Vol. 3, No. 1 ( 2004-01-01), p. 47-58
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 3, No. 1 ( 2004-01-01), p. 47-58
    Abstract: MLN944 (XR5944) is a novel bis-phenazine that has demonstrated exceptional efficacy against a number of murine and human tumor models. The drug was reported originally as a dual topoisomerase I/II poison, but a precise mechanism of action for this compound remains to be determined. Several lines of evidence, including the marginal ability of MLN944 to stabilize topoisomerase-dependent cleavage, and the sustained potency of MLN944 in mammalian cells with reduced levels of both topoisomerases, suggest that other activities of the drug exist. In this study, we show that MLN944 intercalates into DNA, but has no effect on the catalytic activity of either topoisomerase I or II. MLN944 displays no significant ability to stimulate DNA scission mediated by either topoisomerase I or II compared with camptothecin or etoposide, respectively. In addition, yeast genetic models also point toward a topoisomerase-independent mechanism of action. To examine cell cycle effects, synchronized human HCT116 cells were treated with MLN944, doxorubicin, camptothecin, or a combination of the latter two to mimic a dual topoisomerase poison. MLN944 treatment was found to induce a G1 and G2 arrest in cells that is unlike the typical G2-M arrest noted with known topoisomerase poisons. Finally, transcriptional profiling analysis of xenograft tumors treated with MLN944 revealed clusters of regulated genes distinct from those observed in irinotecan hydrochloride (CPT-11)-treated tumors. Taken together, these findings suggest that the primary mechanism of action of MLN944 likely involves DNA binding and intercalation, but does not appear to involve topoisomerase inhibition.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.47.3.1
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2004
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract P5-13-36: Germline BRCA 1/2 and other predisposition genes in high-risk early-stage HR+/HER2- breast cancer (BC) patients treated with endocrine therapy (ET) with or without palbociclib: A secondary analysis from the PENELOPE-B study
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. P5-13-36-P5-13-36
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P5-13-36-P5-13-36
    Abstract: Background: In high-risk hormone-receptor (HR)+/HER2- BC patients germline (g) mutations can be found in approximately 14% in BRCA1/2 and in BRCA1/2 and other BC predisposition genes in 20% (Pohl-Rescigno E, et al. JAMA Oncol 2020). In metastatic BC CDK4/6 inhibitors may have greater activity in patients with a BRCA mutation detected in ctDNA (André F, et al. J Clin Oncol 2020). The PENELOPE-B trial did not to show an improved invasive disease-free survival (iDFS) by adding palbociclib to ET in high-risk HR+/HER2- BC (Loibl S, et al. J Clin Oncol 2021). Methods: Blood samples from 898 of 1250 PENELOPE-B patients were available. 445 patients were sampled following a case-cohort design (220 cases defined as patients with any event during follow-up and 225 randomly selected patients without any event [non-cases]) and analyzed for germline variants in BRCA1/2 and 16 non-BRCA1/2 cancer predisposition genes (ATM, BARD1, BRIP1, CDH1, CHEK2, FANCM, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, XRCC2) by targeted next generation sequencing (NGS). The primary definition of mutational status was the prevalence of a pathogenic mutation (mt) in one or more analyzed BC predisposition genes. Statistical analyses for time-to-event endpoints (iDFS, distant disease-free survival [DDFS] , and overall survival [OS]) were based on inverse probability weighting: weighted Cox proportional hazard models and Kaplan-Meier estimates were used. Results: 442 of 445 patients (placebo arm: 104 cases and 105 non-cases; palbociclib arm: 114 cases and 119 non-cases) were successfully analyzed for mutational status. A total of 42 (9.5%) patients (placebo arm: 9.1%; palbociclib arm: 9.9%) carried any mutation. 15 (3.4%) patients had a gBRCA1/2 mt (one of whom carried a gATM mt and one a gCHEK2 mt in addition to gBRCA2 mt) and 29 (6.6%) had mutations in one of the other BC predisposition genes (n=8 CHEK2, n=7 PALB2, n=5 ATM, n=2 RAD50, n=1 for BARD1, FANCM, MRE11A, RAD51C, RAD51D, TP53 and n=1 both RAD51D and BRIP1). The mutational status with respect to all genes analyzed showed no significant correlation to clinical baseline variables. With regard to gBRCA1 and gBRCA2 genes only, the mutational status significantly correlated with age but not with other clinical variables: all 15 (100%) gBRCA mt carriers were younger than 50 years compared to 238 (56%) wildtype (wt) patients (p=0.002). The iDFS rate after 3 years was 80.9% in patients with any mutation and 79.5% in patients without. Mutational status (mt vs. wt) based on all genes analyzed was not prognostic (iDFS: hazard ratio 1.015, 95%CI 0.558-1.784; DDFS: 0.970, 95%CI 0.521-1.758; OS: 0.768, 95%CI 0.274-1.615). Neither the mutated patients had a benefit from palbociclib treatment (palbociclib vs placebo; iDFS: hazard ratio 0.766, 95%CI 0.263-3.022; DDFS: 0.897, 95%CI 0.275-3.489; OS: 0.666, 95%CI 0.063-5.671) nor the wt patients (iDFS: hazard ratio 0.918, 95%CI 0.650-1.303; DDFS: 0.966, 95%CI 0.679-1.393; OS: 0.901, 95%CI 0.573-1.433); interaction tests for treatment arm/mutational status for all time-to-event endpoints were not statistically significant. Analysis in the subgroups of patients by gBRCA1/2 showed similar results but had less statistical power. Conclusions: In this case-cohort analysis of 442 patients enrolled in the PENELOPE-B trial, the detection of BC predisposition genes was lower than expected with 10%. This is probably due to the low rate of gBRCA1/2 carriers (3.4%), which could be influenced by the selection criteria of the trial. Patients with gBRCA1/2 or other BC disposition genes had a comparable outcome to non-carriers in the PENELOPE-B tr ial. Citation Format: Sibylle Loibl, Jan Hauke, Karen Gelmon, Frederik Marmé, Corinna Ernst, Miguel Martin, Michael Untch, Hervé Bonnefoi, Erik Knudsen, Seock-Ah Im, Angela DeMichele, Laura Van’t Veer, Sung-Bae Kim, Harry Bear, Nicole McCarthy, Nicholas Turner, Agnieszka Witkiewicz, Federico Rojo, Peter A Fasching, José A García-Sáenz, Catherine M Kelly, Toralf Reimer, Masakazu Toi, Hope S Rugo, Carsten Denkert, Michael Gnant, Andreas Makris, Yuan Liu, Olga Valota, Bärbel Felder, Karsten Weber, Valentina Nekljudova, Eric Hahnen. Germline BRCA1/2 and other predisposition genes in high-risk early-stage HR+/HER2- breast cancer (BC) patients treated with endocrine therapy (ET) with or without palbociclib: A secondary analysis from the PENELOPE-B study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-36.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-P5-13-36
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Abstract P4-15-01: Distinct early proliferation response to neoadjuvant anti-HER2 antibody drug conjugate +/- endocrine therapy in early breast cancer in the WSG ADAPT HER2+/HR+ trial
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 9_Supplement ( 2015-05-01), p. P4-15-01-P4-15-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P4-15-01-P4-15-01
    Abstract: Background: HER2+, hormone receptor-positive (HR+) breast cancer is a distinct subtype associated with good prognosis but poor response to standard chemotherapy + anti-HER2 (single or dual blockade). Substantial overtreatment by poly-chemotherapy combined with anti-HER2 therapy is suspected in this subtype. Yet, the efficacy of combining endocrine therapy (ET) with anti-HER2 therapy or novel antibody drug conjugates like T DM1 without systemic chemotherapy remains unclear. Methods: ADAPT HER2+/HR+ is a phase II, randomized, neoadjuvant, 3-arm trial (12 weeks) in patients with cT1c-cT3, cN0/+ HER2+, ER+ and/or PR+ early BC. Arm A: T-DM1 (3.6 mg/kg) alone; Arm B: T DM1 + ET (premenopausal: tamoxifen, postmenopausal: AI); Arm C: trastuzumab + ET. Postoperative chemotherapy is recommended together with completion of one year of trastuzumab. Initial and serial core biopsies were obtained prior to therapy and after 3 weeks. First translational analysis of the trial run-in phase (n=130) focuses on dynamics of HER2, Ki67, ER and PR. Results: 162 tumors, HR+ and HER2+ by local pathology, were screened; n=130 were HR+ and HER2+ by central pathology and randomized at 40 trial sites in Germany between 11/2012 and 03/2014 (Arm A/B/C: 37/49/44). Median age was 49 years; 60% were cT2-3, 32% cN+, 75% central G3; median baseline Ki67 was 30%; 49 patients were treated by TAM and 44 postmenopausal patients by AI in ET containing arms. Three-week core biopsies were available in 117 patients (arm A/B/C: n=33/43/41), n=99 with invasive tumor tissue (61/76 (80%) in T-DM1 containing arms and 38/41(93%) in trastuzumab + ET arm). Three-week Ki67 could only be analyzed in n=73 (53% of patients in T-DM1-containing arms, 81% in the T+ET arm) due to a lacking amount of cells for counting ( & lt;500). Median fractional decrease in proliferation (Ki67) after 3 weeks of therapy was 40% in the T-DM1 + ET arm (B) as compared to 14% and 25% in the T-DM1 (A) and T+ET (C) arms, respectively. Among postmenopausal patients, the contrast (52% (B) vs. 0% (A) and 28% (B)) was significant. Mean PR expression change (absolute, measured in %) was -15 in the B Arm vs. 7 and -7 in the A and C arms, respectively (p=0.04) – particularly in postmenopausal women ( 25 vs. +13 and -10, respectively, p=0.04). Baseline ER expression was positively associated with early proliferation response (fractional Ki67 decrease), e.g., by logistic regression using 30% decrease as response criterion. Data on the impact of gene mutations and further molecular markers on proliferation response will be available for presentation at the meeting. Conclusions: In the unique neoadjuvant ADAPT HER2+/HR+ trial, the combination of T-DM1 with ET (particularly AI) seems to be associated with a strong early proliferation response and PR expression drop in anti-HER2 antibody (drug conjugate) +/- ET, without systemic pre-operative chemotherapy. Interim analysis is scheduled after 130 completely treated patients. The high percentage of non-invasive tissue biopsied after 3 weeks in the T-DM1 arms is intriguing, as it would be consistent with higher pathological complete response rates. Citation Format: Oleg Gluz, Ulrike Nitz, Kuemmel Sherko, Kraemer Stefan, Michael Braun, Claudia Schumacher, Bahriye Aktas, Helmut Forstbauer, Toralf Reimer, Peter Fasching, Jochem Potenberg, Daniel Hofmann, Ronald E Kates, Rachel Wuerstlein, Matthias Christgen, Hans H Kreipe, Nadia Harbeck. Distinct early proliferation response to neoadjuvant anti-HER2 antibody drug conjugate +/- endocrine therapy in early breast cancer in the WSG ADAPT HER2+/HR+ trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS14-P4-15-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Abstract PD17-06: Immunohistochemical markers and determinants of clinical response in the Penelope-B trial
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. PD17-06-PD17-06
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. PD17-06-PD17-06
    Abstract: Background: The Penelope-B trial did not show improvement in invasive disease-free survival (iDFS) with the addition of palbociclib to endocrine therapy (ET) in patients with high-risk early breast cancer (BC) after neoadjuvant chemotherapy (NACT). Biomarkers may be able to identify subgroups of patients deriving benefit from Palbociclib and guide future studies. Estrogen-receptor (ER), progesterone-receptor (PgR) and Ki-67 might be helpful in identifying patients benefiting from palbociclib. Concordantly, tumors with elevated expression of Cyclin D1 and phosphorylated retinoblastoma protein (phospho-RB) may harbor more dependency on CDK4/6 and thus higher sensitivity to palbociclib. Methods: The percentage of positive ER and PgR cells and Ki-67 assessed in surgical specimens after NACT were combined to obtain the immunohistochemical score 3 (IHC3, Cuzick et al JCO 2011, low vs high based on the median IHC3 value). Cyclin D1 and phospho-RB Ser 807/811 immunoreactive (phospho-RB) scores were analyzed in residual tumors after NACT (range 0-12 each). Proportional hazard regression model was used to assess the predictive and prognostic value of IHC3 and treatment on iDFS. Subgroup analysis was performed according to BC intrinsic subtypes (luminal-A/normal-like, luminal-B/HER2-enriched/basal) and HER2-status (HER2 0, HER2 low). Cox/Fine-Gray regression was used to define the predictive and prognostic value of CyclinD1 (≤1, & gt;1), phospho-RB (≤2, & gt;2) as dichotomized and continuous variables on iDFS, distant DFS (DDFS), locoregional invasive recurrence-free interval (LRRFI) and overall survival (OS). Multivariate analyses (MVA) were adjusted for age (≤50 vs & gt;50), Ki-67 (≤15 vs & gt;15), region (non-Asian vs Asian), ypN (ypN0-1 vs ypN2-3), risk status (CPS-EG=2 ypN+ vs ≥3), cT (cT1-2 vs cT3-4), ypT (ypT0-2 vs ypT3-4), and grade (G1-2 vs G3). The MVA for IHC3 includes all the covariates above except Ki-67. p & lt; 0.05 was defined as statistically significant. Results: Data for ER, PgR, Ki-67, HER2, Cyclin D1 and phospho-RB were available for 1250 patients. Overall, 98.9% of the patients had ER+ tumors, 75.0% PgR+, 52.2% had HER2 low, 25.5% Ki-67 & gt;15, 50% had IHC3 score higher than median, 93.9% had Cyclin D1 & gt;1, 57.8% had phospho-RB & gt;2. Patients with IHC3 score high had a worse iDFS compared to patients with IHC3 score low (MVA HR 2.28 95%CI (1.78-2.91), p & lt; 0.0001). Patients with luminal-A/normal-like tumors and IHC3 low had an improved iDFS with the addition of palbociclib to ET (MVA HR 0.35 95%CI (0.14-0.90), test for interaction p=0.01). No difference was observed according to HER2 status. Cyclin D1 & gt;1 has no predictive value but is prognostic for better iDFS (MVA HR 0.62 95%CI (0.41-0.94), p=0.023), LRRFI (MVA HR 0.30 95%CI (0.15-0.63), p=0.001) and OS (MVA HR 0.50 95%CI (0.28-0.89), p=0.019). Similar results were obtained when Cyclin D1 was analysed as a continuous variable. Phospho-RB had neither predictive nor prognostic value. Phospho-RB highly correlates with Ki-67 (p & lt; 0.001, Spearman correlation 0.248). Conclusions: Patients with high Cyclin D1 expression had a favorable prognosis independent of treatment arm, but patients with luminal-A/normal-like tumors and IHC3 low after NACT had an improved outcome when receiving palbociclib in addition to adjuvant ET. Theses exploratory studies suggest specific signatures/phenotypes could predict benefit from Palbociclib in high-risk early breast cancer. Citation Format: Erik S. Knudsen, Sivaramakrishna Rachakonda, Frederik Marmé, Miguel Martín, Michael Untch, Hervé R. Bonnefoi, Wolfgang D. Schmitt, Sung-Bae Kim, Harry D. Bear, Agnieszka Witkiewicz, Seock-Ah Im, Angela DeMichele, Laura Van’t Veer, Nicole McCarthy, Bruno V. Sinn, Karen Gelmon, José Ángel García-Sáenz, Catherine M. Kelly, Toralf Reimer, Nicholas Turner, Federico Rojo, Martin Filipits, Peter A. Fasching, Christian Schem, Lesley-Ann Martin, Yuan Liu, Masakazu Toi, Hope Rugo, Michael Gnant, Andreas Makris, Jenny Furlanetto, Karsten Weber, Carsten Denkert, Sibylle Loibl. Immunohistochemical markers and determinants of clinical response in the Penelope-B trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD17-06.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-PD17-06
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Abstract P4-01-01: RIBANNA 5th interim analysis: Matched-pair analysis of progression-free survival (PFS) across treatment cohorts and comparison of frontline ribociclib + endocrine therapy PFS data from RIBANNA vs MONALEESA trials, in HR+, HER2– ABC
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P4-01-01-P4-01-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P4-01-01-P4-01-01
    Abstract: Background: Ribociclib (RIB) plus endocrine therapy (ET) has demonstrated a statistically significant survival benefit across the three phase 3 MONALEESA (ML) trials, irrespective of menopausal status, line of therapy, or combination partner. RIBANNA (CLEE011ADE03), a prospective, noninterventional study assessing the efficacy and safety of RIB + ET, or ET monotherapy or chemotherapy (CT) in first-line (1L) setting in pre-, peri- and postmenopausal patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) is ongoing in Germany since October 2017 to gain insights into real-world scenario. In the 5th interim analysis (IA) from RIBANNA, a matched-pair analysis of 1L PFS data from the three treatment cohorts and comparison of 1L PFS data on RIB + ET from RIBANNA versus (vs) ML trials will be performed. Methods: Pre-, peri- and postmenopausal women receiving RIB + ET, ET monotherapy, or CT as 1L treatments for HR+, HER2– ABC, in accordance with German treatment guidelines, were included. Propensity score matched (PSM) analysis of PFS data from the 3 treatment cohorts will be conducted to reduce the bias due to confounding variables. In addition to safety analyses, comparison of 1L PFS data on RIB + ET from RIBANNA vs ML trials will be performed. Results: By the cutoff date of the 4th IA (October 11, 2021), data were available for 2187 pts, including 1849 (83.0%), 193 (78.1%), and 145 (73.6%) pts from the RIB + ET, ET monotherapy, and CT cohorts in 1L setting, respectively (Table 1). Of these 2187 pts, 1111 postmenopausal pts received 1L RIB + letrozole; 357 postmenopausal pts received 1L RIB + fulvestrant, and 158 pre- and perimenopausal pts received 1L RIB + anastrazole/letrozole. The unadjusted Kaplan–Meïer estimate for median PFS was 31.7 months (95% confidence interval [CI], 28.5–36.2) in the RIB + ET cohort, 25.7 months (95% CI, 18.0–not reached) in the ET monotherapy cohort, and 15.3 months (95% CI, 9.5–17.5) in the CT cohort. The most frequent treatment-emergent adverse events (grade 3 or 4) in the RIB + ET and ET monotherapy cohorts were neutropenia (14.8% and 6.6%, respectively) while that in CT cohort was general physical health deterioration (9.1%). Conclusions: In RIBANNA, a diverse pt population is being analyzed in a real-world setting; treatment with RIB + ET has been observed to be well adopted. The 5th IA is planned in October 2022 and data will be presented in SABCS 2022, which will include PSM analysis to compare 1L PFS data across treatment cohorts as well as comparison of 1L PFS data on RIB + ET from RIBANNA vs ML trials. The safety profile of RIB was found to be similar to those observed in ML trials. Table 1. Patient demographics and baseline clinical characteristics from the 4th IA. Citation Format: Christian Jackisch, Cosima Brucker, Thomas Decker, Anne Engel, Peter A. Fasching, Thomas Göhler, Jan Janssen, Andreas Köhler, Kerstin Lüdtke-Heckenkamp, Diana Lüftner, Marion van Mackelenbergh, Frederik Marmé, Arnd Nusch, Beate Rautenberg, Toralf Reimer, Marcus Schmidt, Rudolf Weide, Pauline Wimberger, Christian Roos, Achim Wöckel. RIBANNA 5th interim analysis: Matched-pair analysis of progression-free survival (PFS) across treatment cohorts and comparison of frontline ribociclib + endocrine therapy PFS data from RIBANNA vs MONALEESA trials, in HR+, HER2– ABC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-01.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P4-01-01
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    E2F3a Is Critically Involved in Epidermal Growth Factor Receptor–Directed Proliferation in Ovarian Cancer
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 11 ( 2010-06-01), p. 4613-4623
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 11 ( 2010-06-01), p. 4613-4623
    Abstract: We describe for the first time a new integral molecular pathway, linking transcription factor E2F3a to epidermal growth factor receptor (EGFR) activation in ovarian cancer cells. Investigations on the role of E2F family members in EGFR-mediated mitogenic signaling revealed that E2F3a was selectively upregulated following EGFR activation, whereas all other E2F family members remained unaffected. In contrast, EGF treatment of healthy ovarian surface epithelial and mesothelial cells yielded a selective upregulation of proliferation-promoting E2F1 and E2F2 without influencing E2F3a expression. In ovarian cancer cell lines, the extent of EGF-induced proliferative stimulus was closely related to the magnitude of E2F3a increase, and proliferation inhibition by E2F3a knockdown was not overcome by EGF exposure. Furthermore, the EGFR-E2F3a axis was found to be signal transducer and activator of transcription 1/3 dependent and the ratio of IFN-regulatory factor (IRF)-1 to IRF-2 was shown to be determinative for E2F3a control. In a pilot study on 32 primary ovarian cancer specimens, a highly significant correlation between activated EGFR and E2F3a expression was disclosed. This new integral pathway in the EGFR-driven mitogenic cell response, which through its key player E2F3a was found to be essential in triggering proliferation in ovarian cancer cells, provides new insights into EGFR signaling and could represent the basis for appealing new therapeutic approaches in ovarian cancer. Cancer Res; 70(11); 4613–23. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-09-3551
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Abstract P4-01-03: Progression-free survival and patient-reported outcomes in HR+, HER2– ABC patients treated with first-line ribociclib + endocrine therapy (ET) or ET monotherapy or chemotherapy in real world setting: 5th interim analysis of RIBANNA
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P4-01-03-P4-01-03
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P4-01-03-P4-01-03
    Abstract: Background: Ribociclib in combination with endocrine therapy (ET) has demonstrated survival benefits in a broad patient population with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC). RIBANNA (CLEE011ADE03) is an ongoing, prospective, noninterventional study assessing the efficacy and safety of first-line (1L) ribociclib in combination with ET in routine clinical practice in women with HR+, HER2– ABC. This study will provide insights into the use of ribociclib in combination with ET with regard to effectiveness and patient-reported outcomes (PRO) in the real-world setting in a large patient population. Methods: Patients with HR+, HER2– ABC starting their 1L treatment with ribociclib + ET, or ET monotherapy, or chemotherapy (CT) were included. Data after disease progression to second-line (2L) and further lines of therapy are being collected too. The progression-free survival (PFS) in 1L, 2L and PFS2 (time from inclusion into the trial in the 1L setting until progression from 2L to third-line therapy) for individual treatment sequences will be analyzed using the Kaplan–Meier method. PRO for all the patients in the 1L and 2L treatment cohorts are being evaluated using the Morisky Medication Adherence Scale (MMAS-8), questionnaires related to quality-of-life (EORTC QLQ-C30) and its breast cancer–specific module (EORTC QLQ-BR23) as well as the Hospital Anxiety and Depression Scale (HADS). Data were collected at baseline and at every 3 months until the end of treatment. Results: By the cutoff date (October 11, 2021) of the fourth interim analysis, data were available for 2187 patients (Table 1). Overall, 633 patients progressed after 1L therapy, including 27.6%, 30.6%, and 43.4% of patients from the 1L ribociclib + ET, ET monotherapy, and CT cohorts, respectively. A total of 286 patients received CDK4/6 inhibitors in 2L, which represents 48.3%, 37.3%, and 27.0% of patients from the 1L ribociclib + ET, ET monotherapy, and CT cohorts, respectively. The PFS in 1L, 2L and PFS2 results for individual treatment sequences will be presented at SABCS 2022. PRO compliance rates at baseline were 88.2%, 89.8%, and 89.4% for EORTC QLQ-C30 global health status, QLQ-BR23, and HADS-D/A, respectively, in the overall population, and 84.5% for MMAS-8 in the 1L ribociclib + ET cohort. Data for patient-reported adherence to 1L ribociclib + ET and for questionnaires related to global health-related quality of life, functioning, and symptoms from patients receiving treatment in 1L and 2L settings will be analyzed and presented at SABCS 2022. Conclusion: The RIBANNA study has shown diverse population characteristics among patients who received ribociclib treatment in a real-world setting. The 5th interim analysis is planned in October 2022. Data on PFS, PFS2, specific therapy sequences and PRO from 1L and 2L that will provide insights on therapy sequencing strategy will be presented at SABCS 2022. Table 1. Patient disposition at the data cutoff date (October 11, 2021). Citation Format: Peter A. Fasching, Cosima Brucker, Thomas Decker, Anne Engel, Thomas Göhler, Christian Jackisch, Jan Janssen, Andreas Köhler, Kerstin Lüdtke-Heckenkamp, Diana Lüftner, Marion van Mackelenbergh, Frederik Marmé, Arnd Nusch, Beate Rautenberg, Toralf Reimer, Marcus Schmidt, Rudolf Weide, Pauline Wimberger, Christian Roos, Achim Wöckel. Progression-free survival and patient-reported outcomes in HR+, HER2– ABC patients treated with first-line ribociclib + endocrine therapy (ET) or ET monotherapy or chemotherapy in real world setting: 5th interim analysis of RIBANNA [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symp osium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-03.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P4-01-03
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Abstract P1-18-15: Real-world efficacy of ribociclib + aromatase inhibitor/fulvestrant, or endocrine monotherapy, or chemotherapy as first-line treatment in women with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) locally advanced or metastatic breast cancer: Fourth interim analysis from the RIBANNA study
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. P1-18-15-P1-18-15
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P1-18-15-P1-18-15
    Abstract: Background: Ribociclib (RIB; a selective CDK4/6 inhibitor) + endocrine therapy (ET; aromatase inhibitor or fulvestrant along with ovarian suppression in pre- and perimenopausal patients [pts]) received USFDA and EMA approval for pre-, peri- and postmenopausal pts with HR+, HER2- advanced breast cancer (ABC) based on results from phase 3 MONALEESA (ML) trials. In ML-2 trial, first-line treatment (tx) with RIB + letrozole (LET) vs placebo (PBO) + LET significantly improved median progression-free survival (mPFS) in postmenopausal pts with HR+, HER2- ABC. In ML-3 and ML-7 trials, RIB + ET vs PBO + ET showed a significant improvement in mPFS and overall survival among pts with HR+, HER2- ABC, irrespective of menopausal status, line of tx and combination partner. Real-world evidence on the effectiveness, safety, and tolerability of RIB + ET in pts with HR+, HER2- ABC would help to gain insight into routine clinical practice. Methods: RIBANNA is a prospective, noninterventional study ongoing in Germany since October 2017. Pre-, peri- and postmenopausal pts who received first-line tx with RIB + ET, or ET alone or chemotherapy (CT) for HR+, HER2- ABC in accordance with German tx guidelines were included. Data from routine clinical practice in all 3 cohorts, including further lines of sequential therapy, were collected. The third interim analysis data from RIBANNA study was presented in SABCS 2020. Fourth interim analysis data will be presented during SABCS 2021. Results: Till February 11, 2021, 2594 pts were included in the study (RIB + ET, n = 2183; ET, n = 229; CT, n = 182) and the enrollment was stopped; however, pt follow-up will be continued for an additional 4 years. For the fourth interim analysis, full analysis set (comprising all pts, except screening failures and locked pts, who received at least one dose of study medication [safety analysis set] and for whom ≥ 1 post-baseline evaluation was recorded) included 2131 pts (RIB + ET, n = 1814 [81.2%]; ET, n = 175 [73.8%] ; CT, n = 142 [72.1%]), while the safety analysis set comprised 2452 pts (RIB + ET, n = 2062 [92.3%] ; ET, n = 216 [91.1%]; CT, n = 174 [88.3%] ). Until last patient first visit, among 2594 treated pts (including screening failures), data from first-line (1L) tx are available for 2452 pts (94.5%), from second-line (2L) tx for 343 pts (13.2%), and from third-line (3L) tx for 74 pts (2.9%, Table 1). Overall, 23.9%, 27.9%, and 43.4% of pts discontinued the study in RIB + ET, ET, and CT cohorts, respectively. The fourth interim analysis is planned in October 2021, and the final baseline demographic data as well as updated information on safety will be presented during SABCS 2021. Conclusion: RIBANNA study showed diverse population characteristics among pts who received RIB tx in a real-world setting. The data from fourth interim analysis, which is planned in October 2021, including final baseline demographic data and updated safety data will be presented. Table 1. Patient disposition following last patient first visit on February 11, 2021PatientsTotal. (N = 2594). n (%)RIB + AI/FUL (n = 2183). n (%)ET (n = 229). n (%)CT. (n = 182). n (%)Includeda2594 (100.0)2183 (100.0)229 (100.0)182 (100.0)Treated (including screening failures)2452 (94.5)2062 (94.5)216 (94.3)174 (95.6)1L therapyb2452 (94.5)2062 (94.5)216 (94.3)174 (95.6)2L therapyb343 (13.2)264 (12.1)36 (15.7)43 (23.6)3L therapyb74 (2.9)53 (2.4)10 (4.4)11 (6.0)4L therapyb7 (0.3)7 (0.3)0 (0.0)0 (0.0)Discontinued studyc664 (25.6)521 (23.9)64 (27.9)79 (43.4)aAll pts signing informed consent form, bNumber of data set available till February11, 2021, cEnd of documentation with reason other than ‘end of study. Citation Format: Diana Lüftner, Cosima Brucker, Thomas Decker, Peter Fasching, Thomas Göhler, Christian Jackisch, Jan Janssen, Andreas Köhler, Kerstin Lüdtke-Heckenkamp, Marion van Mackelenbergh, Frederik Marmé, Arnd Nusch, Beate Rautenberg, Toralf Reimer, Marcus Schmidt, Rudolf Weide, Pauline Wimberger, Naiba Nabieva, Christian Roos, Achim Wöckel. Real-world efficacy of ribociclib + aromatase inhibitor/fulvestrant, or endocrine monotherapy, or chemotherapy as first-line treatment in women with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) locally advanced or metastatic breast cancer: Fourth interim analysis from the RIBANNA study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-15.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-P1-18-15
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Abstract 2616: Stemness factors nanog and oct4 contribute to epithelial-to-mesenchymal transition and are predictive for outcome in esophageal adenocarcinoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 2616-2616
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 2616-2616
    Abstract: Background and Aims: The incidence of esophageal adenocarcinoma (EAC) has increased six-fold in Western countries over the last decades, and 5-year survival rates remain low at 5-20%. While multimodality treatment strategies for curative treatment of esophageal cancer, including the CROSS regimen (chemoradiotherapy followed by surgery) have increased median overall survival, the majority of patients develop recurrences after several months. Epithelial to mesenchymal transition (EMT) has been recently shown by our group to be one of the major underlying mechanisms of resistance to therapy. Paradoxically, therapeutic pressure of effective therapies such as the CROSS regimen are found to instruct a mesenchymal, resistant phenotype in models for EAC. In this study, the aim was to delineate the heterogeneity for the propensity to undergo EMT after chemoradiation and which mechanisms underpin this propensity. Methods: A panel of 8 EAC cell lines (5 primary and 3 ATCC cell lines) were treated with chemoradiotherapy and ranked by their propensity to undergo EMT, based on morphology when EMT occurred and protein marker expression. Next, the cell line panel as well as 44 pre-treated esophageal biopsies were RNA-sequenced. Expression data of the cell line panel were linked to their ranked in vitro EMT response. By means of Leave-one-out cross validation with Ridge Regression, EMT score prediction in pre-treated biopsies was validated. Gene expression profiles were related to clinical outcome data to identify markers that associated with propensity for EMT in patients. Results: In the panel of in vitro EAC models, a strong heterogeneity was observed for the propensity to EMT after chemoradiation. For each marker, Ridge regression analysis identified the top 50 highly correlating genes. Combining all positively correlating genes of days to EMT, NCAD and ZEB1, known key transcription factors of pluripotency including NANOG and OCT4 emerged. Expression of NANOG and OCT4 in pre-treatment biopsies was highly predictive for response to neoadjuvant chemoradiation, occurrence of recurrences, and survival in patients. Genetic perturbation by knockout and inhibition of NANOG and OCT4 reduced the onset of EMT and sensitized cells for chemoradiation. Conclusions: In conclusion, we were able to identify patients who are disproportionally prone to develop EMT in response to chemoradiation. Moreover, stemness factors NANOG and OCT4 are crucial regulators in plasticity of EAC and are promising predictive markers in pre-treatment biopsies of patients. By targeting NANOG and OCT4 in vitro, cells were sensitized to chemoradiation, holding promise for stemness inhibition to prevent therapy resistance in EAC. Citation Format: Amber Perenna van der Zalm, Mark P. Dings, Reimer Janssen, Peter Bailey, Jan Koster, Danny Zwijnenburg, Richard Volckmann, Cynthia Waasdorp, Jeroen Blokhuis, César Oyarce, Gerrit Hooijer, Sybren L. Meijer, Jan Paul Medema, Hanneke W. van Laarhoven, Maarten F. Bijlsma. Stemness factors nanog and oct4 contribute to epithelial-to-mesenchymal transition and are predictive for outcome in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2616.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-2616
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    Abstract HER2-06: HER2-06 Outcome analysis of HER2-zero or HER2-low hormone receptor-positive (HR+) breast cancer patients - characterization of the molecular phenotype in combination with molecular subtyping
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. HER2-06-HER2-06
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. HER2-06-HER2-06
    Abstract: Background: Breast cancer with low HER2 expression (HER2-low) is of high clinical relevance because of new therapeutic options with antibody-drug conjugates. We have recently shown in a large cohort from neoadjuvant clinical trials that HER2-low breast cancer has different molecular characteristics as well as different clinical outcomes compared to HER2-zero. Considering the positive correlation between HER2-low expression and hormone receptor positivity observed consistently in many investigations, we have extended our analysis to HR+ tumors from the post-neoadjuvant PenelopeB trial. In PenelopeB, patients with HR+ breast cancer and residual disease after neoadjuvant chemotherapy (NACT) were randomized to post-neoadjuvant palbociclib versus placebo in addition to endocrine therapy. We evaluated the molecular phenotype and clinical outcomes of HER2-low compared to HER2-zero patients. Methods: A total of 1250 patients were randomized, HER2 status was available for 1151 tumors from pretherapeutic core biopsy, determined mainly by local pathology, and from 1213 tumors from the post-NACT sample, determined as part of central pathology. For 1119 patients a paired HER2-status was both available. HER2-zero was defined as IHC0 and HER2-low-positive was defined as IHC1+ or IHC2+/ISH-. Gene expression analysis of 2549 genes using the HTG oncology biomarker panel was performed in 620 pretherapeutic biopsies and 780 post-NACT residual tumor samples, with 539 paired gene expression samples. Breast cancer subtypes were determined using the AIMS approach. Results: In pretherapeutic biopsies, 695 tumors (60%) were HER2-low and 457 (40%) were HER2-zero. A HER2-low status in the biopsy was significantly linked to improved iDFS (HR 0.76 (0.60-0.96; p=0.02). In residual tumors, 632 tumors (60%) were HER2-low and 581 (40%) were HER2-zero, without any prognostic impact of HER2 low status. In addition, a shift of HER2-low-status comparing core biopsy and residual tumor was observed in 415 (37%) of 1119 tumors. 161 (14%) had a shift from HER2-zero to HER2-low and 254 (23%) shifted from HER2-low to HER2-zero. A shift from HER2-zero to HER2-low in the post-NACT samples was significantly linked to reduced iDFS (HR 1.43 [95%CI 1.01-2.01]), p=0.04), compared to HER2-low group, while a shift from HER2-low to HER2-zero was associated with better iDFS compared to HER2-zero group, although not statistically significant (p=0.17). We did not observe a significant correlation of HER2-low status and AIMS molecular subtypes. In particular, the HER2-enriched (HER2E) subtype was assigned to only 4.3% of HER2-zero and 3.1% of HER2-low tumors. Significant iDFS differences were observed for HER2-low-status in combination with AIMS subtypes (lumB/basal/HER2E vs. lumA/normL; overall p-value & lt; 0.0001) for both pretherapeutic biopsies and residual tumor. Patients with post-NACT HER2-low tumors had an improved survival in the subgroups of aggressive AIMS subtypes (lumB/basal/HER2E), but not in the less aggressive AIMs subtypes (lumA/normL), with a positive test for interaction (p=0.02). For the pre-NACT samples a similar, but non-significant trend was observed. We evaluated a total of 620 core biopsies for differences in gene expression comparing HER2-low and HER2-zero tumors. A total of 417 genes were statistically significantly different, but in a hierarchical clustering there was no clear separation of HER2-low and HER2-zero tumors. Conclusions: In the PenelopeB cohort of HR+ tumors, a HER2-low status in pretherapeutic core biopsies is related to improved disease-free survival, especially for those tumors that have a more aggressive intrinsic subtype. A shift of HER2-low status was observed before and after chemotherapy, indicating an adaptation of the pathway activity to therapy-induced stress, which might become relevant for future diagnostic and therapeutic approaches. Citation Format: Carsten Denkert, Miguel Martín, Michael Untch, Hervé R. Bonnefoi, Erik S. Knudsen, Seock-Ah Im, Angela DeMichele, Agnieszka Witkiewicz, Laura Van ’t Veer, Sung-Bae Kim, Harry D. Bear, Nicole McCarthy, Karen Gelmon, Frederik Marmé, José Ángel García-Sáenz, Nicholas Turner, Federico Rojo, Martin Filipits, Lesley-Ann Martin, Peter A. Fasching, Christian Schem, Catherine M. Kelly, Toralf Reimer, Masakazu Toi, Hope Rugo, Michael Gnant, Andreas Makris, Yuan Liu, Karsten Weber, Sivaramakrishna Rachakonda, Sibylle Loibl. HER2-06 Outcome analysis of HER2-zero or HER2-low hormone receptor-positive (HR+) breast cancer patients - characterization of the molecular phenotype in combination with molecular subtyping [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr HER2-06.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-HER2-06
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...