Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial.

Abstract

BACKGROUND:

Only human epidermal growth factor receptor (HER)2 status determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has been validated to predict efficacy of HER2-targeting antibody-drug-conjugate trastuzumab emtansine (T-DM1). We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DM1.

PATIENTS AND METHODS:

HER2-positive mBC patients with IHC3+ or FISH ≥ 2.2 scheduled for T-DM1 underwent a pretreatment HER2-positron emission tomography (PET)/computed tomography (CT) with (89)Zr-trastuzumab. [(18)F]2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT was performed at baseline and before T-DM1 cycle 2. Patients were grouped into four HER2-PET/CT patterns according to the proportion of FDG-avid tumor load showing relevant (89)Zr-trastuzumab uptake (>blood pool activity): patterns A and B were considered positive (>50% or all of the tumor load 'positive'); patterns C and D were considered negative (>50% or all of the tumor load 'negative'). Early FDG-PET/CT was defined as nonresponding when >50% of the tumor load showed no significant reduction of FDG uptake (<15%). Negative (NPV) and positive predictive values (PPV) of HER2-PET/CT, early FDG response and their combination were assessed to predict morphological response (RECIST 1.1) after three T-DM1 cycles and time-to-treatment failure (TTF).

RESULTS:

In the 56 patients analyzed, 29% had negative HER2-PET/CT while intrapatient heterogeneity (patterns B and C) was found in 46% of patients. Compared with RECIST1.1, respective NPV/PPV for HER2-PET/CT were 88%/72% and 83%/96% for early FDG-PET/CT. Combining HER2-PET/CT and FDG-PET/CT accurately predicted morphological response (PPV and NPV: 100%) and discriminated patients with a median TTF of only 2.8 months [n = 12, 95% confidence interval (CI) 1.4-7.6] from those with a TTF of 15 months (n = 25, 95% CI 9.7-not calculable).

CONCLUSIONS:

Pretreatment imaging of HER2 targeting, combined with early metabolic response assessment holds great promise for improving the understanding of tumor heterogeneity in mBC and for selecting patients who will/will not benefit from T-DM1.

CLINICALTRIALSGOV IDENTIFIER:

NCT01565200.

• Authors: G Gebhart, L E Lamberts, Z Wimana, C Garcia, P Emonts, L Ameye, S Stroobants, M Huizing, P Aftimos, J Tol, W J G Oyen, D J Vugts, O S Hoekstra, C P Schröder, C W Menke-van der Houven van Oordt, T Guiot, A H Brouwers, A Awada, E G E de Vries, P Flamen
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 27 Issue 4 Pg. 619-24 (Apr 2016) ISSN: 1569-8041 [Electronic] England
• PMID: 26598545 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Antibodies, Monoclonal, Humanized
• Fluorodeoxyglucose F18
• Maytansine
• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab
• Ado-Trastuzumab Emtansine

Topics

• Ado-Trastuzumab Emtansine
• Adult
• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Breast Neoplasms (diagnostic imaging, drug therapy, genetics, pathology)
• Female
• Fluorodeoxyglucose F18 (administration & dosage)
• Humans
• In Situ Hybridization, Fluorescence
• Maytansine (administration & dosage, analogs & derivatives)
• Middle Aged
• Positron-Emission Tomography
• Receptor, ErbB-2 (genetics)
• Trastuzumab
• Treatment Outcome