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Pilot study of 68Ga-DOTA-F(ab')2-trastuzumab in patients with breast cancer.

Beylergil V, Morris PG, Smith-Jones PM, Modi S, Solit D, Hudis CA, Lu Y, O'Donoghue J, Lyashchenko SK, Carrasquillo JA, Larson SM, Akhurst TJ - Nucl Med Commun (2013)

Bottom Line: The one patient who did not receive 68Ga-DOTA-F(ab')2-trastuzumab was excluded from analysis.It was determined that 68Ga-DOTA-F(ab')2-trastuzumab was well tolerated, with a T½ of ≈ 3.6 ± 0.9 h; the critical organ was the kidney, with a mean dose of 0.383 cGy/37 MBq; and tumor targeting was seen in 4/8 patients with HER2-positive disease.The reagent is safe, and assessments through additional studies in a better-defined group of patients, using larger administered masses of antibodies, with a better immunoreactive fraction are needed.

View Article: PubMed Central - PubMed

Affiliation: aDepartment of Radiology, Molecular Imaging and Therapy Service bDepartment of Medicine, Breast Cancer Medicine Service cHuman Oncology and Pathogenesis Program dDepartment of Medical Physics eRadiochemistry and Molecular Imaging Probes Core Facility, Memorial Sloan-Kettering Cancer Center Departments of fRadiology gMedicine, Weill Cornell Medical College, New York, New York, USA.

ABSTRACT

Objective: 68Ga-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-F(ab')2-trastuzumab [68Ga-DOTA-F(ab')2-trastuzumab] has been developed at our institution as a positron imaging reagent for assessing human epidermal growth factor receptor 2 (HER2) expression status by in-vivo imaging. Initial studies on animals demonstrated promising results in the monitoring of treatment response to heat shock protein 90-targeted drugs that inhibit the client protein HER2. We report here our initial clinical experience in the assessment of the toxicity, pharmacokinetics, biodistribution, and dosimetry profile of 68Ga-DOTA-F(ab')2-trastuzumab with PET/computed tomography using a mean of 236 MBq/5 mg administered intravenously.

Materials and methods: A group of 16 women with breast cancer were enrolled in this study. The one patient who did not receive 68Ga-DOTA-F(ab')2-trastuzumab was excluded from analysis. Both HER2-negative (n=7) and HER2-positive (n=8) cases were studied. Among the latter, seven had undergone trastuzumab treatment previously and one had not.

Results: It was determined that 68Ga-DOTA-F(ab')2-trastuzumab was well tolerated, with a T½ of ≈ 3.6 ± 0.9 h; the critical organ was the kidney, with a mean dose of 0.383 cGy/37 MBq; and tumor targeting was seen in 4/8 patients with HER2-positive disease.

Conclusion: The reagent is safe, and assessments through additional studies in a better-defined group of patients, using larger administered masses of antibodies, with a better immunoreactive fraction are needed.

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Related in: MedlinePlus

Serial MIP images (patient 6) displayed at the same relative intensity. Although a slight decrease in blood pool is present, blood pool activity dominates the distribution. At 58, 109, and 189 min the blood pool has SUVmax of 16.9, 13.6, and 9.8, respectively. There is slight increased uptake over time in the liver and kidneys. The patient had HER2-positive disease and was receiving lapatinib. Tumors in the left adrenal, hilar nodes, and bones were not visualized on Ga-PET. HER2, human epidermal growth factor receptor 2; MIP, maximum intensity projection; p.i, postinjection; SUV, standardized uptake value.
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Figure 2: Serial MIP images (patient 6) displayed at the same relative intensity. Although a slight decrease in blood pool is present, blood pool activity dominates the distribution. At 58, 109, and 189 min the blood pool has SUVmax of 16.9, 13.6, and 9.8, respectively. There is slight increased uptake over time in the liver and kidneys. The patient had HER2-positive disease and was receiving lapatinib. Tumors in the left adrenal, hilar nodes, and bones were not visualized on Ga-PET. HER2, human epidermal growth factor receptor 2; MIP, maximum intensity projection; p.i, postinjection; SUV, standardized uptake value.

Mentions: PET images showed significant blood pool retention with corresponding decrease over time (Fig. 2). The kidneys had the highest concentration with a slight increase over time. The liver also had prominent activity with a significant amount accounted for by the blood pool. Although liver activity was stable over time, the liver to blood pool ratio increased, indicating slight concentration (Fig. 3). This relatively intense liver uptake in patients might limit the ability to evaluate hepatic metastases. Although with our method we would not have expected a significant amount of colloid formation or aggregate formation, we have retested the DOTA-F(ab′)2 during 68Ga radiolabeling for colloid using an instant thin-layer chromatography method and none were found. We have also performed a size exclusion high-performance liquid chromatography analysis of the chelated antibody fragment before and after radiolabeling and have found only a small amount of aggregate, which will not explain the concentration of 68Ga observed in the liver (data not shown).


Pilot study of 68Ga-DOTA-F(ab')2-trastuzumab in patients with breast cancer.

Beylergil V, Morris PG, Smith-Jones PM, Modi S, Solit D, Hudis CA, Lu Y, O'Donoghue J, Lyashchenko SK, Carrasquillo JA, Larson SM, Akhurst TJ - Nucl Med Commun (2013)

Serial MIP images (patient 6) displayed at the same relative intensity. Although a slight decrease in blood pool is present, blood pool activity dominates the distribution. At 58, 109, and 189 min the blood pool has SUVmax of 16.9, 13.6, and 9.8, respectively. There is slight increased uptake over time in the liver and kidneys. The patient had HER2-positive disease and was receiving lapatinib. Tumors in the left adrenal, hilar nodes, and bones were not visualized on Ga-PET. HER2, human epidermal growth factor receptor 2; MIP, maximum intensity projection; p.i, postinjection; SUV, standardized uptake value.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3815146&req=5

Figure 2: Serial MIP images (patient 6) displayed at the same relative intensity. Although a slight decrease in blood pool is present, blood pool activity dominates the distribution. At 58, 109, and 189 min the blood pool has SUVmax of 16.9, 13.6, and 9.8, respectively. There is slight increased uptake over time in the liver and kidneys. The patient had HER2-positive disease and was receiving lapatinib. Tumors in the left adrenal, hilar nodes, and bones were not visualized on Ga-PET. HER2, human epidermal growth factor receptor 2; MIP, maximum intensity projection; p.i, postinjection; SUV, standardized uptake value.
Mentions: PET images showed significant blood pool retention with corresponding decrease over time (Fig. 2). The kidneys had the highest concentration with a slight increase over time. The liver also had prominent activity with a significant amount accounted for by the blood pool. Although liver activity was stable over time, the liver to blood pool ratio increased, indicating slight concentration (Fig. 3). This relatively intense liver uptake in patients might limit the ability to evaluate hepatic metastases. Although with our method we would not have expected a significant amount of colloid formation or aggregate formation, we have retested the DOTA-F(ab′)2 during 68Ga radiolabeling for colloid using an instant thin-layer chromatography method and none were found. We have also performed a size exclusion high-performance liquid chromatography analysis of the chelated antibody fragment before and after radiolabeling and have found only a small amount of aggregate, which will not explain the concentration of 68Ga observed in the liver (data not shown).

Bottom Line: The one patient who did not receive 68Ga-DOTA-F(ab')2-trastuzumab was excluded from analysis.It was determined that 68Ga-DOTA-F(ab')2-trastuzumab was well tolerated, with a T½ of ≈ 3.6 ± 0.9 h; the critical organ was the kidney, with a mean dose of 0.383 cGy/37 MBq; and tumor targeting was seen in 4/8 patients with HER2-positive disease.The reagent is safe, and assessments through additional studies in a better-defined group of patients, using larger administered masses of antibodies, with a better immunoreactive fraction are needed.

View Article: PubMed Central - PubMed

Affiliation: aDepartment of Radiology, Molecular Imaging and Therapy Service bDepartment of Medicine, Breast Cancer Medicine Service cHuman Oncology and Pathogenesis Program dDepartment of Medical Physics eRadiochemistry and Molecular Imaging Probes Core Facility, Memorial Sloan-Kettering Cancer Center Departments of fRadiology gMedicine, Weill Cornell Medical College, New York, New York, USA.

ABSTRACT

Objective: 68Ga-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-F(ab')2-trastuzumab [68Ga-DOTA-F(ab')2-trastuzumab] has been developed at our institution as a positron imaging reagent for assessing human epidermal growth factor receptor 2 (HER2) expression status by in-vivo imaging. Initial studies on animals demonstrated promising results in the monitoring of treatment response to heat shock protein 90-targeted drugs that inhibit the client protein HER2. We report here our initial clinical experience in the assessment of the toxicity, pharmacokinetics, biodistribution, and dosimetry profile of 68Ga-DOTA-F(ab')2-trastuzumab with PET/computed tomography using a mean of 236 MBq/5 mg administered intravenously.

Materials and methods: A group of 16 women with breast cancer were enrolled in this study. The one patient who did not receive 68Ga-DOTA-F(ab')2-trastuzumab was excluded from analysis. Both HER2-negative (n=7) and HER2-positive (n=8) cases were studied. Among the latter, seven had undergone trastuzumab treatment previously and one had not.

Results: It was determined that 68Ga-DOTA-F(ab')2-trastuzumab was well tolerated, with a T½ of ≈ 3.6 ± 0.9 h; the critical organ was the kidney, with a mean dose of 0.383 cGy/37 MBq; and tumor targeting was seen in 4/8 patients with HER2-positive disease.

Conclusion: The reagent is safe, and assessments through additional studies in a better-defined group of patients, using larger administered masses of antibodies, with a better immunoreactive fraction are needed.

Show MeSH
Related in: MedlinePlus