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Impact of 68Ga-NOTA-MAL-MZHER2 PET imaging in advanced gastric cancer patients and therapeutic response monitoring

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Clinical PET imaging of human epidermal growth factor receptor 2 (HER2) can noninvasively detect HER2 overexpression in lesions. A novel 68Ga-NOTA-MAL-MZHER2 (68Ga-HER2) affibody was developed for clinical PET/CT, and its safety, tissue dosimetry, ability to detect HER2-positive lesions, and utility for HER2-targeted therapy in patients with advanced gastric cancer (AGC) were evaluated.

Methods

Thirty-four patients with AGC (23 with HER2-positive and 11 with HER2-negative primary lesions) were included and underwent PET/CT after an injection of approximately 3.7 MBq/kg body weight 68Ga-HER2 affibody. Thirteen patients (8 HER2-positive and 5 HER2-negative patients) were scanned at 1, 2, and 3 h post-injection to determine the best imaging timepoint, and the remaining patients were scanned at the optimized timepoint. All patients underwent standard 18F-FDG PET/CT within 7 d to identify viable lesions. The SUVmax of lesions larger than 1.0 cm were analyzed. Five lesion maxima were analyzed for each organ.

Results

(1) The 68Ga-HER2 affibody was safe and effective, and optimal image contrast was observed 2 h post-injection; the average effective absorbed dose was 0.0215 mSv/MBq. (2) The HER2-positive group had significantly higher 68Ga-HER2 affibody uptake than the HER2-negative group (SUVmax 10.7 ± 12.5 vs 3.8 ± 1.7, p = 0.005). The specificity and sensitivity were 100 and 55.4%, respectively, with a SUVmax cutoff value of 6.6. The SUVmax of the lesions ranged from 1.6 to 73.0, suggesting heterogeneity in HER2 expression. (3) 68Ga-HER2 affibody uptake showed an organ-dependent difference in patients with HER2-positive expression. Bone metastases had the highest uptake (SUVmax 40.5 ± 24.9), followed by liver metastases (SUVmax 11.9 ± 3.9) and lymph node metastases (SUVmax 5.6 ± 3.7), while the uptake in other lesions, including in the primary lesion, was relatively lower (SUVmax 7.3 ± 3.7). (4) Patients receiving therapy had a non-significantly lower lesion SUVmax than patients not receiving therapy (SUVmax 8.8 ± 4.9 vs 11.8 ± 15.2) (p = 0.253). Additionally, the 68Ga-HER2 affibody detected positive lesions in 1/11 patients with HER2-negative primary gastric cancer, which was confirmed by second generation gene sequencing. (5) Moreover, ten patients underwent baseline PET/CT followed by targeted anti-HER2 therapy. Patients with lesions showing high avidity to the 68Ga-HER2 affibody showed longer progression-free survival (PFS) than those with lesions showing low avidity (4–9 m vs 2–3 m).

Conclusion

68Ga-HER2 affibody PET/CT is a feasible method to noninvasively detect the HER2 status in AGC patients and enable early detection with a low dose. Ongoing anti-HER2 therapy did not influence 68Ga-HER2 affibody imaging, which allowed repeated evaluations to monitor the HER2 status after anti-HER2 therapy. This method provides an in vivo understanding of AGC biology that will ultimately help oncologists improve individualized therapy plans.

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Abbreviations

HER2:

human epidermal receptor type 2

68Ga-HER2 affibody:

68Ga-NOTA-MAL-MZHER2

MAL:

maleimide

GC:

gastric cancer

AGC:

advanced gastric cancer

FPS:

progression-free survival

IHC:

immunohistochemistry

GEC:

gastroesophageal junction cancer

i.v.:

intravenous injection

h:

hour

FISH:

fluorescent in situ hybridization

DISH:

dual in situ hybridization

PET:

positron emission tomography

68Ga:

Gallium-68

AUCs:

areas under the curve

HPLC:

high-performance liquid chromatography

p.i.:

post-injection

PPV:

positive predictive value

NPV:

negative predictive value

radio-TLC:

radioactive thin-layer chromatography scanner

d:

day

SUVmax :

the maximum single-voxel standardized uptake value

ROIs:

regions of interest

%ID/g:

percent injected dose per gram

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Acknowledgments

The current research was financially supported by the National Key Research and Development Program of China (No. 2017YFC1308900), National Major Scientific and Technological Special Project for “Significant New Drugs Development”(2017ZX09304021), National Natural Science Foundation (31671035, 81472749), Jiangsu Program for Innovation Research Team (CXTDA2017024), Jiangsu Provincial Natural Science Foundation (BK20170204), Jiangsu Health International Exchange Program (JSH-2018-015), Jiangsu talent projects (LGY2017088), Beijing Natural Science Foundation, Jing-Jin-Ji special projects for basic research cooperation (H2018206600), Beijing Excellent Talents Funding (2017000021223ZK33), Beijing Municipal Administration of Hospitals-Yangfan Project (ZYLX201816), Jiangsu Provincial Commission of Health and Family Planning Foundation (H2017031), and Wuxi Commission of Health and Family Planning Foundation (Q201729).

Author information

Author notes

  1. Nina Zhou, Chang Liu, and Xiaoyi Guo contributed equally in this work.

Authors and Affiliations

  1. Department of Nuclear Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, China

    Nina Zhou, Xiaoyi Guo, Hua Zhu & Zhi Yang

  2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China

    Chang Liu, Jifang Gong, Changsong Qi, Xiaotian Zhang & Lin Shen

  3. Jiangsu Institute of Nuclear Medicine, Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Wuxi, 214063, China

    Yuping Xu & Min Yang

Authors
  1. Nina Zhou
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  2. Chang Liu
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  9. Hua Zhu
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Corresponding authors

Correspondence to Min Yang, Hua Zhu, Lin Shen or Zhi Yang.

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Conflict of interest

The authors declare that they have no potential conflict of interests.

Ethical approval

All procedures in this study were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later versions. Informed consent was, or its equivalent, was obtained from all patients included in the study. The clinical study was approved by the Ethics Committee of the Beijing Cancer Hospital (ethical approval no. 2018KT61).

Informed consent

Informed consent was obtained from the 34 individual participants included in this study.

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Zhou, N., Liu, C., Guo, X. et al. Impact of 68Ga-NOTA-MAL-MZHER2 PET imaging in advanced gastric cancer patients and therapeutic response monitoring. Eur J Nucl Med Mol Imaging 48, 161–175 (2021). https://doi.org/10.1007/s00259-020-04898-5

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  • DOI: https://doi.org/10.1007/s00259-020-04898-5

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