Skip to main content
Top
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | NSCLC | Research article

Immuno-PET imaging for non-invasive assessment of cetuximab accumulation in non-small cell lung cancer

Authors: Aiko Yamaguchi, Arifudin Achmad, Hirofumi Hanaoka, Yusri Dwi Heryanto, Anu Bhattarai, Ratianto, Erdene Khongorzul, Rini Shintawati, A. Adhipatria P. Kartamihardja, Ayaka Kanai, Yumi Sugo, Noriko S. Ishioka, Tetsuya Higuchi, Yoshito Tsushima

Published in: BMC Cancer | Issue 1/2019

Login to get access

Abstract

Backgrounds

Overexpression of epidermal growth factor receptor (EGFR) has been established as a valid therapeutic target of non-small cell lung cancer (NSCLC). However, the clinical benefit of cetuximab as an EGFR-targeting drug is still controversial, partially due to the lack of effective means to identify suitable patients. This study aimed to investigate the potential of radiolabeled cetuximab as a non-invasive tool to predict cetuximab accumulation in NSCLC tumor xenografts with varying EGFR expression levels.

Methods

The NSCLC tumors in model mice were subjected to in vivo biodistribution study and positron emission tomography (PET) imaging 48 h after injection of either 111In- or 64Cu-labeled cetuximab. The EGFR expression levels of NSCLC tumors were determined by ex vivo immunoblotting.

Results

We found that tumors with high EGFR expression had significantly higher [111In]In-DOTA-cetuximab accumulation than tumors with moderate to low EGFR expression (P < 0.05). Strong correlations were found between [111In]In-DOTA-cetuximab tumor uptake and EGFR expression level (r = 0.893), and between [64Cu]Cu-DOTA-cetuximab tumor uptake with EGFR expression level (r = 0.915). PET imaging with [64Cu]Cu-DOTA-cetuximab allowed clear visualization of tumors.

Conclusion

Our findings suggest that this immuno-PET imaging can be clinically translated as a tool to predict cetuximab accumulation in NSCLC cancer patients prior to cetuximab therapy.
Literature
1.
go back to reference Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: A Cancer Journal for Clinicians. 3rd ed. 2018;68:7–30. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: A Cancer Journal for Clinicians. 3rd ed. 2018;68:7–30.
2.
go back to reference Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446.CrossRef Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446.CrossRef
3.
go back to reference Pujol J-L, Pirker R, Lynch TJ, Butts CA, Rosell R, Shepherd FA, et al. Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer. Lung Cancer. 2014;83:211–8.CrossRef Pujol J-L, Pirker R, Lynch TJ, Butts CA, Rosell R, Shepherd FA, et al. Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer. Lung Cancer. 2014;83:211–8.CrossRef
4.
go back to reference Amendt C, Staub E, Friese-Hamim M, Storkel S, Stroh C. Association of EGFR expression level and Cetuximab activity in patient-derived Xenograft models of human non-small cell lung Cancer. Clin Cancer Res. 2014;20:4478–87.CrossRef Amendt C, Staub E, Friese-Hamim M, Storkel S, Stroh C. Association of EGFR expression level and Cetuximab activity in patient-derived Xenograft models of human non-small cell lung Cancer. Clin Cancer Res. 2014;20:4478–87.CrossRef
5.
go back to reference Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, KO MD, et al. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018;19:101–14.CrossRef Herbst RS, Redman MW, Kim ES, Semrad TJ, Bazhenova L, KO MD, et al. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol. 2018;19:101–14.CrossRef
6.
go back to reference Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. Tracking the evolution of non–small-cell lung Cancer. N Engl J Med. 2017;376:2109–21.CrossRef Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. Tracking the evolution of non–small-cell lung Cancer. N Engl J Med. 2017;376:2109–21.CrossRef
7.
go back to reference Chae YK, Arya A, Chiec L, Shah H, Rosenberg A, Patel S, et al. Challenges and future of biomarker tests in the era of precision oncology: can we rely on immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) to select the optimal patients for matched therapy? Oncotarget. 2017;8:100863–98.PubMedPubMedCentral Chae YK, Arya A, Chiec L, Shah H, Rosenberg A, Patel S, et al. Challenges and future of biomarker tests in the era of precision oncology: can we rely on immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) to select the optimal patients for matched therapy? Oncotarget. 2017;8:100863–98.PubMedPubMedCentral
8.
go back to reference van Dongen GAMS, Visser GWM, Lub-de Hooge MN, de Vries EG, Perk LR. Immuno-PET: a navigator in monoclonal antibody development and applications. Oncologist. 2007;12:1379–89.CrossRef van Dongen GAMS, Visser GWM, Lub-de Hooge MN, de Vries EG, Perk LR. Immuno-PET: a navigator in monoclonal antibody development and applications. Oncologist. 2007;12:1379–89.CrossRef
9.
go back to reference Bensch F, van der Veen EL, Lub-de Hooge MN, Jorritsma-Smit A, Boellaard R, Kok IC, et al. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat Med. 2018;24:1852–8.CrossRef Bensch F, van der Veen EL, Lub-de Hooge MN, Jorritsma-Smit A, Boellaard R, Kok IC, et al. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat Med. 2018;24:1852–8.CrossRef
10.
go back to reference Kurihara H, Hamada A, Yoshida M, Shimma S, Hashimoto J, Yonemori K, et al. 64Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients. EJNMMI Res. 2015;5:8.CrossRef Kurihara H, Hamada A, Yoshida M, Shimma S, Hashimoto J, Yonemori K, et al. 64Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients. EJNMMI Res. 2015;5:8.CrossRef
11.
go back to reference Eiblmaier M, Meyer LA, Watson MA, Fracasso PM, Pike LJ, Anderson CJ. Correlating EGFR expression with receptor-binding properties and internalization of 64Cu-DOTA-Cetuximab in 5 cervical Cancer cell lines. J Nucl Med. 2008;49:1472–9.CrossRef Eiblmaier M, Meyer LA, Watson MA, Fracasso PM, Pike LJ, Anderson CJ. Correlating EGFR expression with receptor-binding properties and internalization of 64Cu-DOTA-Cetuximab in 5 cervical Cancer cell lines. J Nucl Med. 2008;49:1472–9.CrossRef
12.
go back to reference Achmad A, Hanaoka H, Yoshioka H, Yamamoto S, Tominaga H, Araki T, et al. Predicting cetuximab accumulation in KRAS wild-type and KRAS mutant colorectal cancer using 64Cu-labeled cetuximab positron emission tomography. Cancer Sci. 2011;103:600–5.CrossRef Achmad A, Hanaoka H, Yoshioka H, Yamamoto S, Tominaga H, Araki T, et al. Predicting cetuximab accumulation in KRAS wild-type and KRAS mutant colorectal cancer using 64Cu-labeled cetuximab positron emission tomography. Cancer Sci. 2011;103:600–5.CrossRef
13.
go back to reference Cai W, Chen K, He L, Cao Q, Koong A, Chen X. Quantitative PET of EGFR expression in xenograft-bearing mice using 64Cu-labeled cetuximab, a chimeric anti-EGFR monoclonal antibody. Eur J Nucl Med Mol Imaging. 2007;34:850–8.CrossRef Cai W, Chen K, He L, Cao Q, Koong A, Chen X. Quantitative PET of EGFR expression in xenograft-bearing mice using 64Cu-labeled cetuximab, a chimeric anti-EGFR monoclonal antibody. Eur J Nucl Med Mol Imaging. 2007;34:850–8.CrossRef
14.
go back to reference Aerts HJWL, Dubois L, Perk L, Vermaelen P, van Dongen GAMS, Wouters BG, et al. Disparity between in vivo EGFR expression and 89Zr-labeled Cetuximab uptake assessed with PET. J Nucl Med. 2008;50:123–31.CrossRef Aerts HJWL, Dubois L, Perk L, Vermaelen P, van Dongen GAMS, Wouters BG, et al. Disparity between in vivo EGFR expression and 89Zr-labeled Cetuximab uptake assessed with PET. J Nucl Med. 2008;50:123–31.CrossRef
15.
go back to reference Niu G, Sun X, Cao Q, Courter D, Koong A, Le QT, et al. Cetuximab-based immunotherapy and Radioimmunotherapy of head and neck squamous cell carcinoma. Clin Cancer Res. 2010;16:2095–105.CrossRef Niu G, Sun X, Cao Q, Courter D, Koong A, Le QT, et al. Cetuximab-based immunotherapy and Radioimmunotherapy of head and neck squamous cell carcinoma. Clin Cancer Res. 2010;16:2095–105.CrossRef
16.
go back to reference Hanaoka H, Kuroki M, Yamaguchi A, Achmad A, Iida Y, Higuchi T, et al. Fractionated Radioimmunotherapy with 90Y-labeled fully human anti-CEA antibody. Cancer Biother Radiopharm. 2014;29:70–6.CrossRef Hanaoka H, Kuroki M, Yamaguchi A, Achmad A, Iida Y, Higuchi T, et al. Fractionated Radioimmunotherapy with 90Y-labeled fully human anti-CEA antibody. Cancer Biother Radiopharm. 2014;29:70–6.CrossRef
17.
go back to reference Ping Li W, Meyer LA, Capretto DA, Sherman CD, Anderson CJ. Receptor-binding, biodistribution, and metabolism studies of 64Cu-DOTA-cetuximab, a PET-imaging agent for epidermal growth-factor receptor-positive tumors. Cancer Biother Radiopharm. 2008;23:158–71.CrossRef Ping Li W, Meyer LA, Capretto DA, Sherman CD, Anderson CJ. Receptor-binding, biodistribution, and metabolism studies of 64Cu-DOTA-cetuximab, a PET-imaging agent for epidermal growth-factor receptor-positive tumors. Cancer Biother Radiopharm. 2008;23:158–71.CrossRef
18.
go back to reference Thurber GM, Schmidt M, Wittrup KD. Factors determining antibody distribution in tumors. Trends Pharmacol Sci. 2008;29:1–5.CrossRef Thurber GM, Schmidt M, Wittrup KD. Factors determining antibody distribution in tumors. Trends Pharmacol Sci. 2008;29:1–5.CrossRef
19.
go back to reference Antibody tumor penetration. Transport opposed by systemic and antigen-mediated clearance. Adv Drug Delivery Rev. 2008;60:1421–34.CrossRef Antibody tumor penetration. Transport opposed by systemic and antigen-mediated clearance. Adv Drug Delivery Rev. 2008;60:1421–34.CrossRef
20.
go back to reference Stapleton S, Milosevic M, Allen C, Zheng J, Dunne M, Yeung I, et al. A mathematical model of the enhanced permeability and retention effect for liposome transport in solid tumors. Chuu C-P, editor. PLoS One. 2013;8:e81157–10.CrossRef Stapleton S, Milosevic M, Allen C, Zheng J, Dunne M, Yeung I, et al. A mathematical model of the enhanced permeability and retention effect for liposome transport in solid tumors. Chuu C-P, editor. PLoS One. 2013;8:e81157–10.CrossRef
21.
go back to reference Dijkers EC, Oude Munnink TH, Kosterink JG, Brouwers AH, Jager PL, de Jong JR, et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther. 2010;87:586–92.CrossRef Dijkers EC, Oude Munnink TH, Kosterink JG, Brouwers AH, Jager PL, de Jong JR, et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther. 2010;87:586–92.CrossRef
22.
go back to reference Nayak TK, Regino CAS, Wong KJ, Milenic DE, Garmestani K, Baidoo KE et al. PET imaging of HER1-expressing xenografts in mice with 86Y-CHXA”-DTPA-cetuximab. Eur J Nucl Med Mol Imaging; 2010;37:1368–1376. Nayak TK, Regino CAS, Wong KJ, Milenic DE, Garmestani K, Baidoo KE et al. PET imaging of HER1-expressing xenografts in mice with 86Y-CHXA”-DTPA-cetuximab. Eur J Nucl Med Mol Imaging; 2010;37:1368–1376.
23.
go back to reference van Bueren JJL, Bleeker WK, Bøgh HO, Houtkamp M, Schuurman J, van de Winkel JGJ, et al. Effect of Target Dynamics on Pharmacokinetics of a Novel Therapeutic Antibody against the Epidermal Growth Factor Receptor: Implications for the Mechanisms of Action. Cancer Res. 2006;66:7630–8.CrossRef van Bueren JJL, Bleeker WK, Bøgh HO, Houtkamp M, Schuurman J, van de Winkel JGJ, et al. Effect of Target Dynamics on Pharmacokinetics of a Novel Therapeutic Antibody against the Epidermal Growth Factor Receptor: Implications for the Mechanisms of Action. Cancer Res. 2006;66:7630–8.CrossRef
24.
go back to reference Hoeben BA, Molkenboer-Kuenen JD, Oyen WJ, Peeters WJ, Kaanders JH, Bussink J, et al. Radiolabeled cetuximab: dose optimization for epidermal growth factor receptor imaging in a head-and-neck squamous cell carcinoma model. Int J Cancer. 2011;129:870–8.CrossRef Hoeben BA, Molkenboer-Kuenen JD, Oyen WJ, Peeters WJ, Kaanders JH, Bussink J, et al. Radiolabeled cetuximab: dose optimization for epidermal growth factor receptor imaging in a head-and-neck squamous cell carcinoma model. Int J Cancer. 2011;129:870–8.CrossRef
25.
go back to reference Tamura K, Kurihara H, Yonemori K, Tsuda H, Suzuki J, Kono Y, et al. 64Cu-DOTA-Trastuzumab PET imaging in patients with HER2-positive breast Cancer. J Nucl Med. 2013;54:1869–75.CrossRef Tamura K, Kurihara H, Yonemori K, Tsuda H, Suzuki J, Kono Y, et al. 64Cu-DOTA-Trastuzumab PET imaging in patients with HER2-positive breast Cancer. J Nucl Med. 2013;54:1869–75.CrossRef
26.
go back to reference Menke-van der Houven van Oordt CW, Gootjes EC, Huisman MC, Vugts DJ, Roth C, Luik AM, et al. 89Zr-cetuximab PET imaging in patients with advanced colorectal cancer. Oncotarget. 2015;6:30384–93.PubMedPubMedCentral Menke-van der Houven van Oordt CW, Gootjes EC, Huisman MC, Vugts DJ, Roth C, Luik AM, et al. 89Zr-cetuximab PET imaging in patients with advanced colorectal cancer. Oncotarget. 2015;6:30384–93.PubMedPubMedCentral
27.
go back to reference Pirker R, Pereira JR, Pawel von J, Krzakowski M, Ramlau R, Park K, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012;13:33–42.CrossRef Pirker R, Pereira JR, Pawel von J, Krzakowski M, Ramlau R, Park K, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012;13:33–42.CrossRef
28.
go back to reference Khambata-Ford S, Harbison CT, Hart LL, Awad M, Xu L-A, Horak CE, et al. Analysis of potential predictive markers of Cetuximab benefit in BMS099, a phase III study of Cetuximab and first-line Taxane/carboplatin in advanced non–small-cell lung Cancer. J Clin Oncol. 2010;28:918–27.CrossRef Khambata-Ford S, Harbison CT, Hart LL, Awad M, Xu L-A, Horak CE, et al. Analysis of potential predictive markers of Cetuximab benefit in BMS099, a phase III study of Cetuximab and first-line Taxane/carboplatin in advanced non–small-cell lung Cancer. J Clin Oncol. 2010;28:918–27.CrossRef
Metadata
Title
Immuno-PET imaging for non-invasive assessment of cetuximab accumulation in non-small cell lung cancer
Authors
Aiko Yamaguchi
Arifudin Achmad
Hirofumi Hanaoka
Yusri Dwi Heryanto
Anu Bhattarai
Ratianto
Erdene Khongorzul
Rini Shintawati
A. Adhipatria P. Kartamihardja
Ayaka Kanai
Yumi Sugo
Noriko S. Ishioka
Tetsuya Higuchi
Yoshito Tsushima
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-6238-4

Other articles of this Issue 1/2019

BMC Cancer 1/2019 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine