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

BMC Cancer

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[1] 0000 0001 2157 7667, grid.4795.f, Instituto de Investigacion Sanitaria Gregorio Marañón, CIBERONC, GEICAM, Universidad Complutense, Avda. de Séneca, 2, 28040, Madrid, Spain;0000 0001 2166 9094, grid.412519.a, PUCRS School of Medicine, Av. Ipiranga 6681, 90619-900, Porto Alegre, RS, Brazil;0000 0004 0372 2033, grid.258799.8, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, 606-8501, Sakyo-ku, Kyoto, Japan;0000 0004 0374 1269, grid.417570.0, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland;0000 0004 0443 9942, grid.417467.7, Mayo Clinic, 4500 San Pablo Rd. S, 32224, Jacksonville, FL, USA;0000 0004 0459 7684, grid.477834.b, Guys Hospital and Sarah Cannon Research Institute, Great Maze Pond, SE1 9RT, London, UK;0000 0004 0480 9560, grid.492963.3, Sarah Cannon Research Institute and Tennessee Oncology, PLLC, 250 25th Ave N, 37203, Nashville, TN, USA;0000 0004 1757 3470, grid.5608.b, Department of Surgery, Oncology and Gastroenterology, University of Padova and Istituto Oncologico Veneto, Via Gattamelata 64, 35128, Padova, Italy;Interdisciplinary Oncology Center, Nussbaumstrasse 12, 80336, Munich, Germany;Paul Strauss Cancer Center, 3 Rue de la Porte de l’Hôpital, BP 30042–67065, Strasbourg, France;Postgraduate Medical Education Center, ul. Marymoncka 99, 02-813, Warsaw, Poland;Samsung Medical Centre, 81 Irwon-Ro Gangnam-gu, 06351, Seoul, South Korea;

关键词: Biomarker;    Metastatic breast cancer;    HER2;    MARIANNE;    mRNA;    PIK3CA;    Progression-free survival;    PTEN;    Trastuzumab emtansine;    T-DM1;   

DOI  :  10.1186/s12885-019-5687-0

来源: publisher

【 摘 要 】

BackgroundThe 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.MethodsIn 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.ResultsMedian 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).ConclusionsIn 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.Trial registrationRegistration number: NCT01120184. Date of registration: April 28, 2010 (registered prospectively).

【 授权许可】

CC BY