Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial

Mattia Rediti; Danai Fimereli; Magdalena Mileva; Zéna Wimana; David Venet; Patrick Flamen; Thomas Guiot; Elisabeth G E de Vries; Carolina P Schröder; C Willemien Menke-van der Houven van Oordt; Marion Maetens; Samira Majjaj; Denis Larsimont; Françoise Rothé; Christos Sotiriou; Géraldine Gebhart

doi:10.1158/1078-0432.CCR-24-1007

Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial

Mattia Rediti, Danai Fimereli, Magdalena Mileva, Zéna Wimana, David Venet, Patrick Flamen, Thomas Guiot, Elisabeth G E de Vries, Carolina P Schröder, C Willemien Menke-van der Houven van Oordt, Marion Maetens, Samira Majjaj, Denis Larsimont, Françoise Rothé, Christos Sotiriou^*, Géraldine Gebhart

^*Corresponding author for this work

Personalized Cancer Treatment (PCT)

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

PURPOSE: The ZEPHIR clinical trial evaluated the role of [89Zr]trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). Here, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]trastuzumab and [18F]FDG uptake, and to dissect the mechanisms involved in T-DM1 resistance.

EXPERIMENTAL DESIGN: RNA was extracted from metastasis biopsies obtained in the ZEPHIR trial. HER2-PET/CT and [18F]FDG-PET/CT imaging data of biopsied lesions were integrated with transcriptomic data. Lesions were compared based on the level of [89Zr]trastuzumab uptake as well as on the presence/absence of metabolic response, defined comparing baseline and on-treatment [18F]FDG-PET/CT.

RESULTS: We analyzed matched transcriptomic and molecular/metabolic imaging data for 24 metastases. Genes and pathways involved in extracellular matrix (ECM) organization and glycosylphosphatidylinositol synthesis were enriched in lesions presenting low [89Zr]trastuzumab uptake. [18F]FDG uptake at baseline correlated with proliferation and immune-related processes. Hypoxia and ECM-related processes were enriched in lesions showing no metabolic response to T-DM1, while immune-related processes were associated with high [89Zr]trastuzumab uptake and metabolic response. Gene signatures including differentially expressed genes according to [89Zr]trastuzumab uptake and metabolic response showed predictive value in an external cohort.

CONCLUSIONS: To our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings suggest a role of ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, highlighting the potential of molecular imaging to depict tumor microenvironment features.

Original language	English
Pages (from-to)	110-121
Number of pages	12
Journal	Clinical Cancer Research
Volume	31
Issue number	1
DOIs	https://doi.org/10.1158/1078-0432.CCR-24-1007
Publication status	Published - 6-Jan-2025

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Integrating Molecular Imaging and Transcriptomic Profiling
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Rediti, M., Fimereli, D., Mileva, M., Wimana, Z., Venet, D., Flamen, P., Guiot, T., de Vries, E. G. E., Schröder, C. P., Menke-van der Houven van Oordt, C. W., Maetens, M., Majjaj, S., Larsimont, D., Rothé, F., Sotiriou, C., & Gebhart, G. (2025). Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial. Clinical Cancer Research, 31(1), 110-121. https://doi.org/10.1158/1078-0432.CCR-24-1007

@article{aab4e83aeb0e43eaaa7b969b7aa89700,

title = "Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial",

abstract = "PURPOSE: The ZEPHIR clinical trial evaluated the role of [89Zr]trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). Here, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]trastuzumab and [18F]FDG uptake, and to dissect the mechanisms involved in T-DM1 resistance.EXPERIMENTAL DESIGN: RNA was extracted from metastasis biopsies obtained in the ZEPHIR trial. HER2-PET/CT and [18F]FDG-PET/CT imaging data of biopsied lesions were integrated with transcriptomic data. Lesions were compared based on the level of [89Zr]trastuzumab uptake as well as on the presence/absence of metabolic response, defined comparing baseline and on-treatment [18F]FDG-PET/CT.RESULTS: We analyzed matched transcriptomic and molecular/metabolic imaging data for 24 metastases. Genes and pathways involved in extracellular matrix (ECM) organization and glycosylphosphatidylinositol synthesis were enriched in lesions presenting low [89Zr]trastuzumab uptake. [18F]FDG uptake at baseline correlated with proliferation and immune-related processes. Hypoxia and ECM-related processes were enriched in lesions showing no metabolic response to T-DM1, while immune-related processes were associated with high [89Zr]trastuzumab uptake and metabolic response. Gene signatures including differentially expressed genes according to [89Zr]trastuzumab uptake and metabolic response showed predictive value in an external cohort.CONCLUSIONS: To our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings suggest a role of ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, highlighting the potential of molecular imaging to depict tumor microenvironment features.",

author = "Mattia Rediti and Danai Fimereli and Magdalena Mileva and Z{\'e}na Wimana and David Venet and Patrick Flamen and Thomas Guiot and {de Vries}, {Elisabeth G E} and Schr{\"o}der, {Carolina P} and {Menke-van der Houven van Oordt}, {C Willemien} and Marion Maetens and Samira Majjaj and Denis Larsimont and Fran{\c c}oise Roth{\'e} and Christos Sotiriou and G{\'e}raldine Gebhart",

year = "2025",

month = jan,

day = "6",

doi = "10.1158/1078-0432.CCR-24-1007",

language = "English",

volume = "31",

pages = "110--121",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "AMER ASSOC CANCER RESEARCH",

number = "1",

}

Rediti, M, Fimereli, D, Mileva, M, Wimana, Z, Venet, D, Flamen, P, Guiot, T, de Vries, EGE , Schröder, CP, Menke-van der Houven van Oordt, CW, Maetens, M, Majjaj, S, Larsimont, D, Rothé, F, Sotiriou, C & Gebhart, G 2025, 'Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial', Clinical Cancer Research, vol. 31, no. 1, pp. 110-121. https://doi.org/10.1158/1078-0432.CCR-24-1007

Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial. / Rediti, Mattia; Fimereli, Danai; Mileva, Magdalena et al.
In: Clinical Cancer Research, Vol. 31, No. 1, 06.01.2025, p. 110-121.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1)

T2 - an analysis of the ZEPHIR clinical trial

AU - Rediti, Mattia

AU - Fimereli, Danai

AU - Mileva, Magdalena

AU - Wimana, Zéna

AU - Venet, David

AU - Flamen, Patrick

AU - Guiot, Thomas

AU - de Vries, Elisabeth G E

AU - Schröder, Carolina P

AU - Menke-van der Houven van Oordt, C Willemien

AU - Maetens, Marion

AU - Majjaj, Samira

AU - Larsimont, Denis

AU - Rothé, Françoise

AU - Sotiriou, Christos

AU - Gebhart, Géraldine

PY - 2025/1/6

Y1 - 2025/1/6

N2 - PURPOSE: The ZEPHIR clinical trial evaluated the role of [89Zr]trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). Here, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]trastuzumab and [18F]FDG uptake, and to dissect the mechanisms involved in T-DM1 resistance.EXPERIMENTAL DESIGN: RNA was extracted from metastasis biopsies obtained in the ZEPHIR trial. HER2-PET/CT and [18F]FDG-PET/CT imaging data of biopsied lesions were integrated with transcriptomic data. Lesions were compared based on the level of [89Zr]trastuzumab uptake as well as on the presence/absence of metabolic response, defined comparing baseline and on-treatment [18F]FDG-PET/CT.RESULTS: We analyzed matched transcriptomic and molecular/metabolic imaging data for 24 metastases. Genes and pathways involved in extracellular matrix (ECM) organization and glycosylphosphatidylinositol synthesis were enriched in lesions presenting low [89Zr]trastuzumab uptake. [18F]FDG uptake at baseline correlated with proliferation and immune-related processes. Hypoxia and ECM-related processes were enriched in lesions showing no metabolic response to T-DM1, while immune-related processes were associated with high [89Zr]trastuzumab uptake and metabolic response. Gene signatures including differentially expressed genes according to [89Zr]trastuzumab uptake and metabolic response showed predictive value in an external cohort.CONCLUSIONS: To our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings suggest a role of ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, highlighting the potential of molecular imaging to depict tumor microenvironment features.

AB - PURPOSE: The ZEPHIR clinical trial evaluated the role of [89Zr]trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). Here, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]trastuzumab and [18F]FDG uptake, and to dissect the mechanisms involved in T-DM1 resistance.EXPERIMENTAL DESIGN: RNA was extracted from metastasis biopsies obtained in the ZEPHIR trial. HER2-PET/CT and [18F]FDG-PET/CT imaging data of biopsied lesions were integrated with transcriptomic data. Lesions were compared based on the level of [89Zr]trastuzumab uptake as well as on the presence/absence of metabolic response, defined comparing baseline and on-treatment [18F]FDG-PET/CT.RESULTS: We analyzed matched transcriptomic and molecular/metabolic imaging data for 24 metastases. Genes and pathways involved in extracellular matrix (ECM) organization and glycosylphosphatidylinositol synthesis were enriched in lesions presenting low [89Zr]trastuzumab uptake. [18F]FDG uptake at baseline correlated with proliferation and immune-related processes. Hypoxia and ECM-related processes were enriched in lesions showing no metabolic response to T-DM1, while immune-related processes were associated with high [89Zr]trastuzumab uptake and metabolic response. Gene signatures including differentially expressed genes according to [89Zr]trastuzumab uptake and metabolic response showed predictive value in an external cohort.CONCLUSIONS: To our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings suggest a role of ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, highlighting the potential of molecular imaging to depict tumor microenvironment features.

U2 - 10.1158/1078-0432.CCR-24-1007

DO - 10.1158/1078-0432.CCR-24-1007

M3 - Article

C2 - 39470686

SN - 1078-0432

VL - 31

SP - 110

EP - 121

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 1

ER -

Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial

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