npj Breast Cancer (Jan 2024)

Molecular imaging predicts lack of T-DM1 response in advanced HER2-positive breast cancer (final results of ZEPHIR trial)

  • Magdalena Mileva,
  • Elisabeth G. E. de Vries,
  • Thomas Guiot,
  • Zéna Wimana,
  • Anne-Leen Deleu,
  • Carolien P. Schröder,
  • Yolene Lefebvre,
  • Marianne Paesmans,
  • Sigrid Stroobants,
  • Manon Huizing,
  • Philippe Aftimos,
  • Jolien Tol,
  • Winette T. A. Van der Graaf,
  • Wim J. G. Oyen,
  • Danielle J. Vugts,
  • C. Willemien Menke-van der Houven van Oordt,
  • Adrienne H. Brouwers,
  • Martine Piccart-Gebhart,
  • Patrick Flamen,
  • Géraldine Gebhart

DOI
https://doi.org/10.1038/s41523-023-00610-6
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 10

Abstract

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Abstract Efficacy of the human epidermal growth factor receptor (HER)2-targeting trastuzumab emtansine (T-DM1) in breast cancer (BC) relies on HER2 status determined by immunohistochemistry or fluorescence in-situ hybridization. Heterogeneity in HER2 expression, however, generates interest in “whole-body” assessment of HER2 status using molecular imaging. We evaluated the role of HER2-targeted molecular imaging in detecting HER2-positive BC lesions and patients unlikely to respond to T-DM1. Patients underwent zirconium-89 (89Zr) trastuzumab (HER2) PET/CT and [18F]-2-fluoro-2-deoxy-D-glucose (FDG) PET/CT before T-DM1 initiation. Based on 89Zr-trastuzumab uptake, lesions were visually classified as HER2-positive (visible/high uptake) or HER2-negative (background/close to background activity). According to proportion of FDG-avid tumor load showing 89Zr-trastuzumab uptake (entire/dominant part or minor/no part), patients were classified as HER2-positive and HER2-negative, respectively. Out of 265 measurable lesions, 93 (35%) were HER2-negative, distributed among 42 of the 90 included patients. Of these, 18 (19%) lesions belonging to 11 patients responded anatomically (>30% decrease in axial diameter from baseline) after three T-DM1 cycles, resulting in an 81% negative predictive value (NPV) of the HER2 PET/CT. In combination with early metabolic response assessment on FDG PET/CT performed before the second T-DM1 cycle, NPVs of 91% and 100% were reached in predicting lesion-based and patient-based (RECIST1.1) response, respectively. Therefore, HER2 PET/CT, alone or in combination with early FDG PET/CT, can successfully identify BC lesions and patients with a low probability of clinical benefit from T-DM1.