PMID- 26598545 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20220408 IS - 1569-8041 (Electronic) IS - 0923-7534 (Linking) VI - 27 IP - 4 DP - 2016 Apr TI - 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. PG - 619-24 LID - 10.1093/annonc/mdv577 [doi] AB - 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. CI - (c) The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Gebhart, G AU - Gebhart G AD - Institut Jules Bordet-Universite Libre de Bruxelles (ULB), Brussels, Belgium geraldine.gebhart@bordet.be. FAU - Lamberts, L E AU - Lamberts LE AD - University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. FAU - Wimana, Z AU - Wimana Z AD - Institut Jules Bordet-Universite Libre de Bruxelles (ULB), Brussels, Belgium. FAU - Garcia, C AU - Garcia C AD - Institut Jules Bordet-Universite Libre de Bruxelles (ULB), Brussels, Belgium. FAU - Emonts, P AU - Emonts P AD - Institut Jules Bordet-Universite Libre de Bruxelles (ULB), Brussels, Belgium. FAU - Ameye, L AU - Ameye L AD - Institut Jules Bordet-Universite Libre de Bruxelles (ULB), Brussels, Belgium. FAU - Stroobants, S AU - Stroobants S AD - Antwerp University Hospital, Antwerpen, Belgium. FAU - Huizing, M AU - Huizing M AD - Antwerp University Hospital, Antwerpen, Belgium. FAU - Aftimos, P AU - Aftimos P AD - Institut Jules Bordet-Universite Libre de Bruxelles (ULB), Brussels, Belgium. FAU - Tol, J AU - Tol J AD - Radboud University Medical Center Nijmegen, Nijmegen. FAU - Oyen, W J G AU - Oyen WJ AD - Radboud University Medical Center Nijmegen, Nijmegen. FAU - Vugts, D J AU - Vugts DJ AD - VU University Medical Center Amsterdam, Amsterdam, The Netherlands. FAU - Hoekstra, O S AU - Hoekstra OS AD - VU University Medical Center Amsterdam, Amsterdam, The Netherlands. FAU - Schroder, C P AU - Schroder CP AD - University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. FAU - Menke-van der Houven van Oordt, C W AU - Menke-van der Houven van Oordt CW AD - VU University Medical Center Amsterdam, Amsterdam, The Netherlands. FAU - Guiot, T AU - Guiot T AD - Institut Jules Bordet-Universite Libre de Bruxelles (ULB), Brussels, Belgium. FAU - Brouwers, A H AU - Brouwers AH AD - University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. FAU - Awada, A AU - Awada A AD - Institut Jules Bordet-Universite Libre de Bruxelles (ULB), Brussels, Belgium. FAU - de Vries, E G E AU - de Vries EG AD - University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. FAU - Flamen, P AU - Flamen P AD - Institut Jules Bordet-Universite Libre de Bruxelles (ULB), Brussels, Belgium. LA - eng SI - ClinicalTrials.gov/NCT01565200 PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151123 PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0Z5B2CJX4D (Fluorodeoxyglucose F18) RN - 14083FR882 (Maytansine) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - P188ANX8CK (Trastuzumab) RN - SE2KH7T06F (Ado-Trastuzumab Emtansine) SB - IM CIN - Ann Oncol. 2016 Apr;27(4):555-7. PMID: 26802154 CIN - Nature. 2017 Mar 29;543(7647):743-746. PMID: 28358075 MH - Ado-Trastuzumab Emtansine MH - Adult MH - Aged MH - Antibodies, Monoclonal, Humanized/*administration & dosage MH - Breast Neoplasms/*diagnostic imaging/*drug therapy/genetics/pathology MH - Female MH - Fluorodeoxyglucose F18/administration & dosage MH - Humans MH - In Situ Hybridization, Fluorescence MH - Maytansine/administration & dosage/*analogs & derivatives MH - Middle Aged MH - Positron-Emission Tomography MH - Receptor, ErbB-2/*genetics MH - Trastuzumab MH - Treatment Outcome OTO - NOTNLM OT - HER2 imaging OT - HER2-positive breast cancer OT - prediction of T-DM1 efficacy EDAT- 2015/11/26 06:00 MHDA- 2016/12/15 06:00 CRDT- 2015/11/25 06:00 PHST- 2015/10/29 00:00 [received] PHST- 2015/11/17 00:00 [accepted] PHST- 2015/11/25 06:00 [entrez] PHST- 2015/11/26 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] AID - S0923-7534(19)35742-4 [pii] AID - 10.1093/annonc/mdv577 [doi] PST - ppublish SO - Ann Oncol. 2016 Apr;27(4):619-24. doi: 10.1093/annonc/mdv577. Epub 2015 Nov 23.