Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2–positive advanced breast cancer: Final results from MARIANNE

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Untersuchungen am Kernporen-Komplex während der Apoptose

Die Behandlung von HeLa 229-Zellen mit TRAIL oder Etoposid führte zu einer charakteristischen apoptotischen Morphologie, zur proteolytischen Aktivierung der Exekutionscaspasen 3 und 7 sowie zu oligonukleosomaler DNA Fragmentierung. Diese Apoptose-spezifische Veränderungen wurden durch den Pancaspasen- Inhibitor z-VAD-fmk gehemmt. Allerdings verlief die Apoptose nach Etoposid- Behandlung viel langsamer als nach Stimulation mit TRAIL. Durch Synchronisierung der Zellen mittels eines doppelten Thymidin-Blocks konnte eine Population in der S-phase des Zellzyklus erhalten werden, die nach DNA-Schaden annähernd synchron und in kurzer Zeit die Apoptose durchlief. Dies ermöglichte einen direkteren Vergleich der Etoposid- und der TRAIL-induzierten Apoptose in Bezug auf den Abbau der Kernpore. Während der Etoposid-induzierten Apoptose in synchronisierten HeLa-Zellen konnten Chromatinkondensation, proteolytische Aktivierung der Exekutionscaspasen 3 und 7, oligonukleosomale DNA Fragmentierung, Cytochrom C Freisetzung und mitochondriale Bax-Translokation beobachtet werden. Weiterhin wurden diese Apoptose-Endpunkte nicht von der Synchronisation per se beeinflusst. Ein konstanter Set von Nukleoporinen, darunter die peripheren Proteine Nup153, RanBP2, Nup214/CAN und Nup50 sowie die Subkomplex-Nukleoporine Nup96 und Nup93 wurden sowohl in der TRAIL als auch in der Etoposid-induzierten Apoptose gespalten. Die Proteolyse war abhängig von Caspasen, da z-VAD-fmk die Nukleoporinspaltung sowohl in der rezeptorvermittelten als auch in der DNA Schaden-induzierten Apoptose unterdrückte. Die Spaltung der Kernporenproteine erfolgte parallel zur Proteolyse von bekannten Caspasesubstraten wie Lamin B und PARP. Allerdings scheint PARP im Etoposid-Modell durch caspaseunabhängige Mechanismen prozessiert zu werden. Zwischen den beiden untersuchten Apoptosemodellen bestanden eine Reihe von Gemeinsamkeiten bezüglich der Reihenfolge der Nukleoporindegradation. Nup93 und Nup96 wurden früh, Tpr und Nup153 wurden gleichzeitig und Nup214/CAN wurde in beiden Apoptosemodellen spät gespalten. Wenn die Apoptose an der Plasmamembran ausgelöst wurde war die Reihenfolge der Spaltung die folgende: Nup93 und Nup96 - Nup153, Tpr und RanBP2 - Nup214/CAN und Nup50. Wurde die Apoptose im Kern induziert ergab sich die folgende Sequenz: Nup93, Nup96, Nup153 und Tpr - RanBP2 und Nup50 - Nup214/CAN

Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer

The Correction to this article has been published in BMC Cancer 2019 19:620Background: The phase III EMILIA and TH3RESA trials demonstrated clinical benefits of trastuzumab emtansine (T-DM1) therapy in patients with previously treated HER2-positive metastatic breast cancer (MBC). Data from these and other trials showed that T-DM1–associated survival benefits were observed across biomarker subgroups tested in these trials. Prespecified, exploratory analyses of the phase III MARIANNE study examined the effects of HER2-related biomarkers on PFS in patients administered T-DM1 in the first-line MBC setting. Methods: In MARIANNE, patients with previously untreated HER2-positive MBC were randomized (1:1:1) to trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab. Biomarker subgroups included HER2 and HER3 mRNA expression levels (≤median vs. >median), HER2 staining intensity (IHC 3+ vs. 2+ vs. 0/1+), PIK3CA status (mutated vs. non-mutated), PTEN H-score (≤median vs. >median), and PTEN protein expression level (0 vs. 1+ vs. 2+ vs. 3+ vs. 4+). PFS was analyzed descriptively for each subgroup using Kaplan–Meier methodology. Additional exploratory post-hoc analyses evaluated the effects of HER2 heterogeneity. Multivariate analyses were also performed. Results: Median PFS was numerically longer for patients with HER2 mRNA levels >median versus ≤median across treatment arms. In general, there were no predictive biomarkers of benefit for either T-DM1 treatment arm; most hazard ratios were close to 1 with wide confidence intervals that included the value 1. Focal HER2 expression (IHC 3+ or IHC 2+) was present in 3.8% of patients and was associated with numerically shorter PFS in the T-DM1–containing treatment arms versus trastuzumab plus taxane. Compared with non-mutated PIK3CA, mutated PIK3CA was associated with numerically shorter median PFS across treatment groups. Post-hoc multivariate analysis showed HER2 mRNA expression and mutated PIK3CA were prognostic for PFS (P ≤ 0.001 for both biomarkers). Conclusions: In MARIANNE, biomarkers related to the HER2 pathway did not have predictive value for PFS when comparing T-DM1 (with or without pertuzumab) with trastuzumab plus taxane. However, HER2 mRNA level and PIK3CA mutation status showed prognostic value. Evaluation of other potential biomarkers, including immune markers, is ongoing

Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: Primary results from the phase III MARIANNE study

Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) –targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer. </jats:sec

Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial

Background HER2-positive metastatic breast cancer is incurable and new treatments are needed. Addition of atezolizumab to trastuzumab emtansine might potentiate anticancer immunity and enhance the HER2-targeted cytotoxic activity of trastuzumab emtansine. We aimed to test this combination in HER2-positive advanced breast cancer that had progressed after previous treatment with trastuzumab and a taxane. Methods The KATE2 study is a randomised, double-blind, placebo-controlled, phase 2 study at 68 centres from nine countries across Asia, Australia, North America, and western Europe. Eligible patients were adults (aged >= 18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and centrally confirmed, measurable, HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Patients were randomly assigned (2:1) either trastuzumab emtansine (3.6 mg/kg of bodyweight) plus atezolizumab (1200 mg) or trastuzumab emtansine plus placebo; all study drugs were administered by intravenous infusion every 3 weeks. Randomisation was done via an interactive voice and web response system using a permuted block scheme (block size of six) and was stratified by PD-L1 status, world region, and liver metastases. Patients, investigators, and study team members were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02924883, and the study has been completed. Findings Between Sept 26, 2016, and Aug 7, 2017, 330 patients were screened for the study, of whom 202 were randomly allocated either atezolizumab (n=133) or placebo (n=69). At the recommendation of the independent data monitoring committee, treatment assignment was unmasked on Dec 11, 2017, due to futility and the numerically higher frequency of adverse events among patients assigned atezolizumab. This date was set as the clinical cutoff for the primary analysis. Median follow-up was 8.5 months (IQR 6.1-11.5) for patients assigned atezolizumab and 8.4 months (5.3-11.1) for those assigned placebo. Median progression-free survival was 8.2 months (95% CI 5.8-10.7) for patients assigned atezolizumab versus 6.8 months (4.0-11.1) for those assigned placebo (stratified hazard ratio 0.82, 95% CI 0.55-1.23; p=0.33). The most common grade 3 or worse adverse events were thrombocytopenia (17 [13%] among 132 patients who received atezolizumab vs three [4%] among 68 who received placebo), increased aspartate aminotransferase (11 [8%] vs two [3%]), anaemia (seven [5%] vs 0), neutropenia (six [5%] vs three [4%]), and increased alanine aminotransferase (six [5%] vs two [3%]). Serious adverse events occurred in 43 (33%) of 132 patients who received atezolizumab and 13 (19%) of 68 patients who received placebo. One patient who received atezolizumab died due to a treatment-related adverse event (haemophagocytic syndrome). Interpretation Addition of atezolizumab to trastuzumab emtansine did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events. Further study of trastuzumab emtansine plus atezolizumab is warranted in a subpopulation of patients with PD-L1-positive, HER2-positive advanced breast cancer. Copyright (C) 2020 Elsevier Ltd. All rights reserved